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ApoE Primer: News on Sulfatide and Insulin Links, Synaptic Damage and Molten Globules
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17 January 2003. While the hunt for new Alzheimer's disease genes continues apace, researchers are still struggling to understand the exact modus operandi of the one prize they have had in hand for years: the lipid carrier protein ApoE. Aiding in the maintenance and repair of neurons, this 34 kD protein on chromosome 19 comes in three common alleles: E2, E3, and E4. The last allele is known to contribute strongly to the great majority of AD cases by bringing on earlier onset and accelerating the cognitive decline. It also is less potent at supporting the brain’s attempt to regenerate from injury. However, just how ApoE4 functions in AD remains hotly contested. The hypothesis that ApoE exerts its main effect through amyloid plaque deposition is perhaps a leading contender that continues to evolve (see below). At the same time, other ideas abound and no explanation is as yet broadly accepted across the field. This story highlights some recent developments in an attempt to stimulate new discussion. (See Keith Crutcher's meeting summary and live discussion for prior coverage).
ApoE3 Protects Against Synaptic Damage Even before Plaques Form
In the December 15 Journal of Neuroscience, Manuel Buttini, working with Lennart Mucke and colleagues at the Gladstone Institute of Neurological Diseases, University of California, San Francisco, and elsewhere, describe provocative findings suggesting that some of apoE4's detrimental effects may have little to do with plaques (Buttini et al., 2002). A large body of prior work has demonstrated that apoE4 binds Aβ avidly and promotes fibril formation and plaque deposition (see, for example, Sanan et al., 1994; Rebeck, 1993; Bales et al., 1997; and Holtzman et al., 2000). And yet, Jacob Raber et al. have found that mice that are double transgenic for human APP/ApoE4-but not mice expressing hAPP and ApoE3-show a spatial memory deficit already at a young adult age when they do not yet contain plaques (Raber et al., 2000; see also Hartman et al., 2001). Mucke's group is working to test their hypothesis that ApoE3 protects against damage that nondeposited Aβ wreaks on synapses and cholinergic pathways early on in the disease. This is part of the lab's broader interest in the pathogenic mechanisms causing early cognitive deficits in AD.
In this study, Buttini et al. studied the interplay of human Aβ with different human ApoE isoforms in aging mice. To do so, they created transgenic mice that express mutant human APP, plus neuronally expressed human ApoE (either 3 or 4), but no mouse ApoE. The researchers then analyzed immunoreactivity for synaptophysin-a marker for presynaptic terminals-in the hippocampus and neocortex, as well as choline acetyltransferase activity in the medial septum, and immunohistochemistry of cholinergic fibers. These measures, they write, correlate better with cognitive dysfunction in AD than does plaque distribution (see, for example, Terry et al., 1991).
Buttini et al. conclude that ApoE3, but not E4, can delay synaptic damage wrought by a combination of increasing age and Aβ. They found a decline in the number of synaptophysin-positive terminals and fibers, which was associated with deficits in synaptic transmission strength in six different genotypes tested. In both neocortex and hippocampus, human APP expression caused a synaptic deficit between six/seven and 12/15 months of age. Importantly, this began prior to plaque deposition. Concurrent human ApoE3 expression delayed this deficit until around 19 months of age, but ApoE4 did not.
In very old mice, ApoE3 no longer protected against synaptic deficits. At this age, the hAPP/ApoE3 transgenics had similar synaptic and cholinergic deficits as the hAPP/ApoE4 mice, even though they had fewer plaques. In the neocortex, the synaptic and cholinergic loss occurred even though few plaques formed there. All these findings do not correlate synaptic damage with plaques very well. Rather, they imply that the different abilities of ApoE3 and E4 to protect synapses play out early and independently of plaque deposition. ApoE4’s effect on plaque deposition, and its attendant neuritic dystrophy, may occur later, these authors suggest.
"This pattern is reminiscent of what happens in humans, where ApoE3 and ApoE4 have their greatest impact on Alzheimer risk between the ages of 45 and 65, with less of an impact seen in older persons," said Mucke. "Although we confirmed previous reports that ApoE4 promotes plaque formation more than ApoE3, our study suggests that this is not all there is to the ApoE4-Alzheimer link. Plaque-independent mechanisms are likely involved as well, or are even more important."
How Does ApoE3 Protect Synapses?
Here, candidate mechanisms include the promotion of neurite outgrowth. Researchers have shown years ago that ApoE3 promotes neurite outgrowth better than E4 in cultured embryonic neurons and cell lines (Nathan et al., 1994, and others since then). Last February, Britto Nathan extended his original research to cortical neurons cultured from adult mice by using a method developed by Greg Brewer at Southern Illinois University School of Medicine. They showed that neurons cultured from adult ApoE knockout mice have shorter neurites than neurons from adult wild-type mice, and that adding human ApoE3 increased neurite outgrowth while adding ApoE4 decreased it. They suggest that this effect might involve the low-density lipoprotein receptor-related protein LRP (Nathan et al., 2002). Two months later, Bruce Teter working with Greg Cole at University of California, Los Angeles, published results of organotypic slice cultures of the hippocampus from ApoE3- or E4-transgenic mice. Experiments changing the expression levels of E3 and E4 suggest to these researchers that E4's outgrowth inhibition results not just from the lack of E3's growth-promoting effect, but from a negative gain of function in E4 (Teter et al., 2002).
Plaques Behind Conspiracy of Head Injury and ApoE
If all this implies to you that plaques are a mere sideshow in the ApoE-AD connection, read on. David Holtzman’s lab at Washington University in St. Louis, Missouri, has bred a series of double-transgenic mice similar to those of the Mucke lab, except that they express human ApoE in astrocytes, not in neurons. (In the human brain, glial cells are the main cell type in brain that synthesizes apoE, notes Holtzman.) His lab has focused its analysis of these mice more on Aβ metabolism and the process of plaque formation, which begins around 15 months of age in these animals, as well as on the relationship of plaques to dystrophic neurites (see ARF related news story and scroll to Holtzman). In the December 1 Journal of Neuroscience, first author Richard Hartman et al. report on the relationship between ApoE4 and traumatic brain injury Hartman et al., 2002. Both these factors increase the risk of developing AD in humans. There is evidence that they act synergistically; for example, ApoE4 carriers are 10 times more likely to develop AD after sustaining a traumatic brain injury, while ApoE4 alone “only” doubles their AD risk (Tang et al. 1996).
To study whether this interaction occurs via Aβ or via other effects on cell death and tissue injury, Hartmann et al. subjected PDAPP/hApoE double-transgenic mice to a head injury model originally developed in Tracy McIntosh'sgroup. They did so when the mice were 9-10 months old and then analyzed the mice’s brains for Aβ deposition, tissue shrinkage, and cell loss three months later, still prior to this strain’s typical age of Aβ deposition. The brain injury, it turned out, accelerated Aβ deposition more strongly in PDAPP/ApoE4 than in E3 mice. Fifty-six percent of the E4 mice had diffuse Aβ deposits and 44 percent had fibrillar plaques, whereas only 20 percent of the E3 mice had deposited diffuse Aβ, and none had mature plaques. By contrast, volume measurements and neuronal counts in the hippocampus and the cortex were similar between the genotypes. This suggests that the higher dementia risk of ApoE4 carriers after TBI is due, in part, to interactions between ApoE and Aβ, the authors write. They caution, however, that this relationship is complex, as ApoE is also involved in Aβ clearance (see Fagan et al., 2002). In both Mucke’s and Holtzman’s labs, hAPP-transgenic mice that do not also express human ApoE deposit more Aβ than double-transgenics of either the ApoE3 or 4 genotype. Hartmann et al. note that while ApoE isoforms clearly contribute to premature earlier amyloid deposition, this alone is probably not sufficient to cause dementia. They suspect that neuritic dystrophy associated with plaques, as well as other factors including oligomer formation, tangle formation, and synaptic loss, contribute to cognitive dysfunction.
Leaking Lysosomes: Molten Globule Gets the Blame
Let’s switch gears and turn to a more reductionist, biophysical view of ApoE. Last June, Zhong-Sheng Ji, working with Robert Mahley, Karl Weisgraber, and others at UCSF’s Gladstone Institute, added another candidate mechanism for how apoE isoforms might differ in their function (Ji et al., 2002). They analyzed the interaction of different ApoE isoforms with Aβ in cultured neuronal cells transfected to produce low levels of ApoE. They found that, together with Aβ42, ApoE4 made these cells’ lysosomes prone to leakage. This potentiated DNA fragmentation and death, probably via links to lysosomal proteases and their ability to activate caspases, as well as release of cytochrome C from mitochondria. ApoE3 was not protective in this assay. Researchers led by Charles Glabe had previously shown that Aβ accumulates in lysosomes and is slowly degraded there, but also disrupts their membranes (Burdick et al., 1997; Yang et al., 1998). ApoE shuttles in and out of neurons, but Ji et al. saw the lysosomal leakage and death only when ApoE was inside the neurons. The authors speculate that ApoE4 potentiates this lysosomal toxicity because it is more prone than ApoE3 to form a particular intermediate state, namely, the partially unfolded conformation referred to as a molten globule (Dobson, 2001). Some researchers believe that these reactive species represent a distinct thermodynamic state a protein can assume. Molten globules retain many features of the native state’s secondary structure, but do not adopt its tertiary structure, and they have more internal mobility than the fully folded protein. Molten globules bind to phospholipids, transfer through membranes, and interfere with membrane processes, the authors write. (For background read, for example, Bychkova and Ptitsyn, 1995.) Ji et al. speculate that in AD, ApoE4 might form such a structure, which then disrupts lysosomal membranes together with Aβ42. At the lysosomal pH4, ApoE4 becomes more unstable and reactive than ApoE3, Ji et al. write.
In the December 27 Journal or Biological Chemistry, Julie Morrow of Weisgraber’s group, and colleagues, follow up with experiments suggesting that ApoE4 indeed forms such a molten globule more readily than E3 or E2 Morrow et al., 2002. Morrow et al. first analyzed the process by which ApoE isoforms denature when treated with urea, and then used structural tools to characterize the different states. At pH4.0, ApoE4 denatured in a three-step fashion, with an intermediate plateau populated by a monomeric version of the protein that resembles a molten globule. In this conformation, the four-helix bundle of ApoE’s amino-terminal domain is opened to expose an otherwise hidden hydrophobic core. ApoE2 never assumed this intermediate state, and ApoE3 did so only under more harshly denaturing conditions.
Researchers are increasingly beginning to detect molten globules and realize that they can play important roles in physiological processes such as protein trafficking and translocation across membranes, Morrow et al. write. For example, human apolipoprotein A-1 can occur as a molten globule (Gursky and Atkinson, 1996). Mutations affecting the formation or stability of the molten globule state can interfere with their normal physiological roles. In Alzheimer’s, this conformation of ApoE4 could alter lipid transport across membranes and in this way help explain why ApoE4 is less able to support neurite outgrowth and neuronal repair after injury, Morrow et al. speculate. Researchers should also consider whether this conformation might disrupt lysosomal membranes, and whether its exposed β, structure might explain ApoE4’s proposed action as a “pathological chaperone” promoting β-sheet and fibril formation of Aβ (Gallo et al., 1994).
IDE: New Link Connecting ApoE and Aβ Degradation to Insulin
On a different front, a paper in this month’s American Journal of Pathology joins together ApoE with Aβ-degrading enzymes, introducing a potential new mechanism by which ApoE could affect AD risk Cook et al., 2002. David Cook, working with Suzanne Craft, Jerry Schellenberg, and others at the Veteran Affairs Puget Sound Health Care System and the University of Washington in, Seattle, report that levels of insulin-degrading enzyme (IDE), one of the handful of proteases implicated in Aβ degradation, are down by about half in AD patients of the ApoE4 genotype compared with ApoE2- and ApoE3-carriers. The researchers quantified protein and mRNA levels of this enzyme in different hippocampal subregions of postmortem brain slices from 26 patients with LOAD and 15 normal adults.
Lower IDE levels in ApoE4 carriers could presumably reduce Aβ degradation, especially intracellularly, leaving more of it around to aggregate. But how would ApoE4 reduce IDE levels? "At this point, we have no solid leads as to how or whether ApoE4 causes reduced IDE, or whether both are related to some other pathophysiological process," said Craft.
Craft et al. had previously shown that AD patients had changes in their insulin metabolism that varied depending on ApoE status. Specifically, they had shown that AD patients of the ApoE2 and 3 genotype had insulin resistance and an altered CSF/plasma insulin ratio, while AD patients with the ApoE4 genotype had normal peripheral insulin levels and metabolism. At first blush, this might seem contradictory; however, Craft et al. combine these findings into a proposed model for further testing. It goes like this: ApoE3/3 AD patients are more likely to have high levels of peripheral insulin, which disrupts the plasma/CSF insulin ratio and causes insulin resistance. These high levels of insulin act as a competitive inhibitor of Aβ degradation by IDE, even though these patients have normal IDE levels. Conversely, ApoE4 patients have low IDE levels, so that even though they may have normal insulin levels, there is insufficient IDE to degrade enough Aβ. "Thus, you can get to the same endpoint in two ways: by having high insulin levels that inhibit IDE activity, which we believe is more common for ApoE3/3 AD patients, or by having low IDE levels, which we believe is more common for ApoE4 patients," said Craft.
Those who have both low IDE and hyperinsulinemia would suffer a double whammy. Last April, Lenore Launer and colleagues reported a greatly increased AD risk in diabetic adults who carry ApoE4 among adults in the Honolulu-Asia Aging Study (Peila et al., 2002; ARF Ab degradation chat; ARF insulin-related chat; Craft ARF news story).
Sphingolipids and APP Processing: ApoE Meddles Here, Too
A separate and fascinating new line of investigation just became even more interesting, thanks to an added ApoE angle. This research looks at the role of sphingolipids and their metabolism (such as sulfatide and its hydrolytic product, ceramide) in APP processing. Available online in manuscript form at the Journal of Biological Chemistry, a new paper by Xianlin Han et al. from Washington University, St. Louis, Missouri, reports that ApoE strongly affects the content of one particular type of sphingolipid, namely sulfatide (Han et al., 2002). This ester of galactocerebroside, made primarily by oligodendrocytes, is a major component of myelin. It has long been known that accumulating sulfatide causes a form of leukodystrophy. But Han, with John Morris and others at Washington University, had reported last August that in people who had died after being diagnosed with very early AD, sulfatide of the gray matter was depleted by up to 93 percent, while the levels of most other lipid classes were normal. This appeared to result not from a defect in sulfatide biosynthesis, but from increased degradation, as these patients' ceramide content was up threefold (Han et al., 2002). While linking a sulfatide decrease and ceramide increase to mild dementia, this study did not implicate ApoE. Han's present JBC paper does that.
The researchers used electrospray ionization mass spectrometry to compare the levels of sulfatide (and a range of other phospholipids, sphingolipids, and cholesterol) in the brains of ApoE knockout mice, David Holtzman’s human ApoE3- and E4-transgenic mice, and CSF from people with different ApoE isoforms. ApoE affected none of the other lipids, but appeared to lower sulfatide content strongly in an isoform-dependent fashion. Further studies examining the carriers of these sulfatides suggest that it associates specifically with ApoE-containing high-density lipoproteins (HDL), which presumably pick up oligodendrocyte-derived sulfatide after their release from astrocytes, Han et al. speculate. The authors also write that their paper is the first to show that ApoE, indeed, as was proposed years ago by Weisgraber and others, regulates lipid transport and metabolism not only in the plasma, as is well-known, but also in the brain.
This new proposed role for ApoE is all the more intriguing, as other ongoing work is implicating ceramide in APP processing. At last year’s Neuroscience conference in Orlando, both Dora Kovacs' group at the Massachusetts General Hospital in Charlestown, and Mark Mattson’s group at the NIA in Baltimore, Maryland, presented data suggesting that rising ceramide levels in neurons correlate with increased Ab generation in an age-related fashion. Mattson presented a hypothesis integrating accumulating sphingomyelins with oxidative stress, which would lead to more ceramide and ACAT activity (see ARF related news story and scroll down to Kovacs). Luigi Puglielli, working with Kovacs, did not observe changes in ACAT activity in response to changing ceramide levels, but rather proposed an effect of ceramide on BACE stabilization. If confirmed and expanded, such work would point to a molecular pathway for how age-related changes in membrane lipid composition, perhaps compounded by ApoE isoform, could lead over time to excessive Ab generation in cases of LOAD. Finally, for a current study on ApoE isoform effects on HDL metabolism, see Hopkins et al., 2002.
Lipids, of course, are also implicated in Ab toxicity via their peroxidation. The three different isoforms of ApoE differ in cysteine residues. Ward Pedersen and Mark Mattson have published data showing that the ApoE2 and ApoE3 isoforms are much more effective in binding to a toxic product of lipid peroxidation called 4-hydroxynonenal (Pedersen et al., 2000). Mattson suggests that ApoE2 and ApoE3 may protect neurons against being damaged and killed by Ab by binding 4-hydroxynonenal with its cysteine residues. (ApoE4 lacks the cysteines, ApoE3 has one cysteine and ApoE2 has two.) Mattson and colleagues had previously demonstrated a key role for membrane lipid peroxidation in the neurotoxic action of Ab.
This ApoE update does not presume to be comprehensive, and the writer invites everyone to fill gaping holes by e-mailing Gabrielle@alzforum.org about other recent work that appears particularly relevant. Yet, even this partial summary shows plainly that the manifold aspects of ApoE’s functions form a complex kaleidoscope of clues and glimpses. Is the challenge now to find the one most important to the development of Alzheimer's? More likely, the truth involves several overlapping and synergistic functions, making the challenge one of assembling the pieces into a big picture that enlightens everyone. Brilliant minds out there, step up to the plate!-Gabrielle Strobel.
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Comment by: Karl Weisgraber
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Submitted 23 January 2003
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Posted 23 January 2003
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I would like to add an important piece to the ApoE4 story, namely ApoE4 domain interaction. Since protein function is directly linked to protein structure and biophysical properties, our studies have focused on determining how ApoE4 differs from ApoE3 and ApoE2. One of the differences is protein stability and the formation of a molten globule state mentioned in the news story. However, a second difference is that ApoE4 exhibits interaction between its two structural domains, referred to as ApoE4 domain interaction. This interaction results from a change in the conformation of arginine at position 61, which both ApoE3 and ApoE4 share. This conformational change is the result of an arginine at 112 in ApoE4 versus a cysteine at this position in ApoE3. X-ray structural analysis and site-directed mutagenesis show that in this interaction, ApoE4’s arginine at position 61 in the amino-terminal domain interacts with glutamic acid in the carboxyl-terminal domain. We hypothesized that this interaction alters the conformation of ApoE4 and may also be a contributing factor, along with molten...
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I would like to add an important piece to the ApoE4 story, namely ApoE4 domain interaction. Since protein function is directly linked to protein structure and biophysical properties, our studies have focused on determining how ApoE4 differs from ApoE3 and ApoE2. One of the differences is protein stability and the formation of a molten globule state mentioned in the news story. However, a second difference is that ApoE4 exhibits interaction between its two structural domains, referred to as ApoE4 domain interaction. This interaction results from a change in the conformation of arginine at position 61, which both ApoE3 and ApoE4 share. This conformational change is the result of an arginine at 112 in ApoE4 versus a cysteine at this position in ApoE3. X-ray structural analysis and site-directed mutagenesis show that in this interaction, ApoE4’s arginine at position 61 in the amino-terminal domain interacts with glutamic acid in the carboxyl-terminal domain. We hypothesized that this interaction alters the conformation of ApoE4 and may also be a contributing factor, along with molten globule formation, to the detrimental effects of ApoE4 in both neurodegeneration and heart disease. See Dong and Weisgraber, 1996 for details.
We have engineered mouse ApoE to reflect this property [PNAS (2001) 98 11587]. Mouse ApoE behaves like human ApoE3 because it lacks the critical arginine 61; it contains the equivalent of arginine 112 and glutamic acid 255. Using gene-targeting we introduced arginine 61, and the mutant mouse ApoE exhibited properties mirroring human ApoE4. Thus, this mouse is a model for this specific property of ApoE4. This mouse mutant does not form a molten globule. A search for small molecule inhibitors that Bob Mahley and I are leading is based on the concept of interfering with ApoE4 domain interaction.
 View all comments by Karl Weisgraber |
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Comment by: Daniel Michaelson
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Submitted 29 January 2003
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Posted 29 January 2003
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The increasing number of isoform-specific pathological effects of ApoE4, which were so effectively reviewed by Gabrielle Strobel, suggest that ApoE4 may exert its pathological effects by several different mechanisms whose relative importance are context-dependent.
In order to assess this possibility, we reviewed the published information regarding the phenotypic effects of the ApoE genotype on neuronal maintenance and repair in ApoE transgenic mice. The results thus obtained (see table below) are from three different lines of transgenic mice that express ApoE either in both neurons and astrocytes, or in only one of these cell types, and which were exposed to aging, (4-6,8,9) head injury,2 excitotoxicity, 7 brain inflammation3 and environmental stimulation1 paradigms. The nine different paradigms thus examined yielded three phenotypic categories which are each defined by the phenotypes of the four mice groups used in these studies, namely ApoE3- and ApoE4-transgenic mice, control and ApoE-deficient mice.
Accordingly, the...
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The increasing number of isoform-specific pathological effects of ApoE4, which were so effectively reviewed by Gabrielle Strobel, suggest that ApoE4 may exert its pathological effects by several different mechanisms whose relative importance are context-dependent.
In order to assess this possibility, we reviewed the published information regarding the phenotypic effects of the ApoE genotype on neuronal maintenance and repair in ApoE transgenic mice. The results thus obtained (see table below) are from three different lines of transgenic mice that express ApoE either in both neurons and astrocytes, or in only one of these cell types, and which were exposed to aging, (4-6,8,9) head injury,2 excitotoxicity, 7 brain inflammation3 and environmental stimulation1 paradigms. The nine different paradigms thus examined yielded three phenotypic categories which are each defined by the phenotypes of the four mice groups used in these studies, namely ApoE3- and ApoE4-transgenic mice, control and ApoE-deficient mice.
Accordingly, the "ApoE gain of toxic function" category corresponds to paradigms in which ApoE4 confers a negative phenotype (e.g., increased mortality) relative to the control, ApoE3 transgenic and ApoE-deficient mice. The second category is "ApoE4 loss of function;" it corresponds to paradigms in which control and ApoE3 transgenic mice have the same phenotype, whereas ApoE deficiency and the ApoE4 genotype are associated with loss of this phenotypic feature. The third and less frequent category is "ApoE3 gain of function" and is associated with a gain of function in the ApoE3 transgenic mice (e.g., enhanced recovery following head trauma) relative to the three other mice groups. Interestingly, the transgenic mice that express ApoE in neurons as well as astrocytes display both the ApoE4 gain-of-toxic-function and ApoE4 loss-of-function phenotypes. In contrast, transgenic mice that express ApoE only in neurons display the ApoE4 loss-of-function phenotype, whereas those that express ApoE only in astrocytes are associated with an ApoE4 gain-of-toxic-function phenotype. This suggests that the pathological effects of ApoE4 on neuronal maintenance and repair are mediated by several mechanisms whose expression and cellular targets may be context- and paradigm-dependent. In addition to Alzheimer’s disease, ApoE4 plays a role in the pathogenesis of multiple sclerosis and several other diseases,10 and it remains to be determined which of the ApoE4-related mechanisms mediate the phenotypic effects of the ApoE4 genotype in these diseases.—Danny Michaelson, Tel-Aviv University, Israel.
References:
References:
1. Levi, U. and Michaelson, D.M. (2000) Proceedings of the 32nd Meeting of the Society for Neuroscience.
2. Sabo T et al. Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: the allele E3 is neuroprotective whereas E4 increases fatalities. Neuroscience 2000;101(4):879-84. Abstract
3. Ophir G et al. Neurobiol. of Diseases. 2003. In press.
4. Veinbergs et al. Differential neurotrophic effects of apolipoprotein E in aged transgenic mice. Neurosci Lett 1999 Apr 23;265(3):218-22. Abstract
5. Buttini M et al. Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein Edepends on isoform, aging, and overexpression of amyloidbetapeptides but not on plaque formation. J Neurosci2002Dec15;22(24):10539-48. Abstract
6. Raber J et al. Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females.
Proc Natl Acad Sci U S A 1998 Sep 1;95(18):10914-9. Abstract
7. Buttini M et al. Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. J Neurosci 1999 Jun 15;19(12):4867-80. Abstract
8. Hartman R et al. Behavioral phenotyping of GFAP-apoE3 and -apoE4 transgenic mice: apoE4 mice show profound working memory impairments in the absence of Alzheimer's-like neuropathology. Exp Neurol 2001 Aug;170(2):326-44. Abstract
9. Holtzman DM et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7. Abstract
10. Chapman J et al. The effects of APOE genotype on age at onset and progression of neurodegenerative diseases. Neurology 2001 Oct 23;57(8):1482-5. Abstract
View all comments by Daniel Michaelson |
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Related Paper: Apolipoprotein E4 influences amyloid deposition but not cell loss after traumatic brain injury in a mouse model of Alzheimer's disease.
Comment by: Eddie Koo, ARF Advisor
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Submitted 7 December 2002
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Posted 7 December 2002
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 I recommend this paper
Another thorough analysis of the PDAPP mice from the Holtzman lab. If one believes the human data and inferences, then these results are predictable. But it is satisfying that the animal results are consistent with the human data. View all comments by Eddie Koo |
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Related Paper: Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation.
Comment by: Fred Van Leuven (Disclosure)
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Submitted 25 February 2003
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Posted 25 February 2003
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This study by L. Mucke and co-workers deserves credit for analyzing the "ApoE-isoform effect" in AD, a problem that is far from understood at the physiological level.
The interesting results are situated on two levels:(i)synaptic deficit is evident in non-plaque bearing APP mice and (ii)ApoE3 but not ApoE4 delays the age- and Aß-dependent synaptic deficits.
The early synaptic deficits are indeed independent of plaque formation, since they are evident in the form of decreased LTP and defective cognition (water-maze and object recogition) in APP-mice long before plaques form (Moechars et al, JBC, 1999, 274:6483-6492) and in mice that lack neuronal PS1 (Dewachter et al, J Neurosci., 2002, 22:3445-53). This is likely due to defective calcium-homeostasis (Herms et al, JBC, 2003, 275: 2484-2489). That "AD is a synaptic disease" has thereby been demonstrated, at least in the mouse models that we have generated over the years.
A note of caution to the second conclusion is in place: the mice express the human ApoE isoforms in neurons as driven by the neuron-specific enolase gene...
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This study by L. Mucke and co-workers deserves credit for analyzing the "ApoE-isoform effect" in AD, a problem that is far from understood at the physiological level.
The interesting results are situated on two levels:(i)synaptic deficit is evident in non-plaque bearing APP mice and (ii)ApoE3 but not ApoE4 delays the age- and Aß-dependent synaptic deficits.
The early synaptic deficits are indeed independent of plaque formation, since they are evident in the form of decreased LTP and defective cognition (water-maze and object recogition) in APP-mice long before plaques form (Moechars et al, JBC, 1999, 274:6483-6492) and in mice that lack neuronal PS1 (Dewachter et al, J Neurosci., 2002, 22:3445-53). This is likely due to defective calcium-homeostasis (Herms et al, JBC, 2003, 275: 2484-2489). That "AD is a synaptic disease" has thereby been demonstrated, at least in the mouse models that we have generated over the years.
A note of caution to the second conclusion is in place: the mice express the human ApoE isoforms in neurons as driven by the neuron-specific enolase gene promoter. Neuronal expression of ApoE, as originally hypothesised by Alan Roses, does affect neuronal functions and integrity by intefering with tau and micro-tubular transport (Tesseur et al, Am J Pathol.,2000,156:951-964 and 157:1495-1510). It is evident and even likely that this would affect synaptic functioning and confound the observations, which need therefore further analysis to confirm their importance. View all comments by Fred Van Leuven |
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Related News: It’s a RAP—Loss of LRP Increases Amyloid Deposition in Mice
Comment by: G. William Rebeck
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Submitted 2 November 2002
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Posted 2 November 2002
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Over the last 10 years, numerous studies have indicated that the low-density lipoprotein receptor-related protein (LRP) may be important for the pathogenesis of Alzheimer's disease. These include studies showing that LRP can internalize membrane-bound forms of the amyloid precursor protein and cause increased Aβ production, and studies showing LRP can internalize Aβ bound to ApoE and α2-macroglobulin, causing increased Aβ clearance. One in vivo study that has been missing is the analysis of Aβ deposition in knockout LRP mouse models of AD. This study has not been possible, since LRP knockouts are not viable. However, Van Uden et al. took the interesting approach of studying mice that have the LRP-associated protein, RAP, knocked out. RAP is important for the maturation and trafficking of LRP, and RAP knockout mice have dramatically reduced levels of LRP. Van Uden et al. analyzed Aβ deposition RAP knockout mice crossed with APP transgenic mice. There were three possible outcomes to this study: no effect on Aβ, Aβ goes down, or Aβ goes...
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Over the last 10 years, numerous studies have indicated that the low-density lipoprotein receptor-related protein (LRP) may be important for the pathogenesis of Alzheimer's disease. These include studies showing that LRP can internalize membrane-bound forms of the amyloid precursor protein and cause increased Aβ production, and studies showing LRP can internalize Aβ bound to ApoE and α2-macroglobulin, causing increased Aβ clearance. One in vivo study that has been missing is the analysis of Aβ deposition in knockout LRP mouse models of AD. This study has not been possible, since LRP knockouts are not viable. However, Van Uden et al. took the interesting approach of studying mice that have the LRP-associated protein, RAP, knocked out. RAP is important for the maturation and trafficking of LRP, and RAP knockout mice have dramatically reduced levels of LRP. Van Uden et al. analyzed Aβ deposition RAP knockout mice crossed with APP transgenic mice. There were three possible outcomes to this study: no effect on Aβ, Aβ goes down, or Aβ goes up. The first outcome would probably not be published. The second outcome (Aβ down) would support the hypothesis that LRP is more important for internalization of full-length APP, leading to production of Aβ. The third outcome (Aβ up) would support the hypothesis that LRP is more important for the clearance of Aβ. The results of Van Uden et al. support this last hypothesis. They found significantly more Aβ deposited in RAP knockout mouse brains at 10 and 18 months, and significantly higher amounts of Aβ42. The study was well controlled. The authors showed in RAP knockout mice, there were no changes in total APP levels, in the distribution of APP in the brain, in astrocyte activation, or in MAP2-positive dendrites. There was, however, the expected dramatic (80 percent) reduction in LRP levels. The authors point out that there was also a decrease in another receptor family member, the LDL receptor, and presumably in other family members. Thus, there is the possibility that other receptors besides LRP are responsible for the clearance of Aβ. But the main finding, that ApoE receptors act as a clearance mechanism for Aβ in the brain, is strongly supported. View all comments by G. William Rebeck |
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Benjamin Wolozin, ARF Advisor (Disclosure)
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Submitted 19 February 2004
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Posted 19 February 2004
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This article provides an intriguing link among aging, oxidation, ceramides, and cholesterol. Mark Mattson’s group analyzed the brain content of sphingomyelin and ceramides in young and old animals. They observed a striking >100-fold increase in the levels of C24:0 galactosyl-ceramide in old C57B6 mice compared to young (three-month-old) mice. In contrast, the amount of C24:0 sphingomyelin was less in six-month-old mice than in 24-month-old mice. Other small changes were observed, including a modest increase in C24:0 ceramide and even small increases in free cholesterol. The group went on to show similar changes in Alzheimer's brain and in hippocampal neurons following treatment with Aβ; they also show that treating the neurons with antioxidants or ISP-1 (an inhibitor of sphingomyelin synthesis) prevents the accumulation of these species.
Ceramides are known to stimulate apoptosis, and inhibition of ceramide production would be expected to be protective. In this context, the moderate increase in C24:0 ceramide could be deleterious for the neuron. Similarly, the modest...
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This article provides an intriguing link among aging, oxidation, ceramides, and cholesterol. Mark Mattson’s group analyzed the brain content of sphingomyelin and ceramides in young and old animals. They observed a striking >100-fold increase in the levels of C24:0 galactosyl-ceramide in old C57B6 mice compared to young (three-month-old) mice. In contrast, the amount of C24:0 sphingomyelin was less in six-month-old mice than in 24-month-old mice. Other small changes were observed, including a modest increase in C24:0 ceramide and even small increases in free cholesterol. The group went on to show similar changes in Alzheimer's brain and in hippocampal neurons following treatment with Aβ; they also show that treating the neurons with antioxidants or ISP-1 (an inhibitor of sphingomyelin synthesis) prevents the accumulation of these species.
Ceramides are known to stimulate apoptosis, and inhibition of ceramide production would be expected to be protective. In this context, the moderate increase in C24:0 ceramide could be deleterious for the neuron. Similarly, the modest increase in cholesterol might also be deleterious because increased cholesterol is associated with increased Aβ production. However, a critical question is the site of cholesterol production. Increased cholesterol associated with myelin would be less significant than increases in neuronal cholesterol. Prior studies provide conflicting reports on cholesterol levels in Alzheimer’s disease. Most studies do not find a general disease-related increase in cholesterol, although several studies have noted increases in neuronal cholesterol in AD and increases in plaque-associated cholesterol (1-3).
The most striking aspect of this manuscript is >100-fold increase in galactosyl-ceramide levels. A quick perusal of the literature suggests that galactosyl-ceramide increases when production of glucosyl-ceramide is inhibited, and that galactosyl-ceramide is protective (4). Thus, the increased production of galactosyl-ceramide might be a protective response to oxidative damage in aging.
References:
1. Heverin M, Bogdanovic N, Lutjohann D, Bayer T, Pikuleva I, Bretillon L, Diczfalusy U, Winblad B, Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J Lipid Res. 2004 Jan;45(1):186-93. Epub 2003 Oct 01. Abstract
2. Co-localization of cholesterol, apolipoprotein E and fibrillar Abeta in amyloid plaques. Brain Res Mol Brain Res. 2003 Jan 31;110(1):119-25. Abstract
3. Distl R, Meske V, Ohm TG. Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol (Berl). 2001 Jun;101(6):547-54.
Abstract
4. Grazide S, Terrisse AD, Lerouge S, Laurent G, Jaffrezou JP. Cytoprotective effect of glucosylceramide synthase inhibition against daunorubicin induced apoptosis in human leukemic cell lines. J Biol Chem. 2004 Feb 6 [Epub ahead of print] Abstract
View all comments by Benjamin Wolozin |
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Luigi Puglielli
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Submitted 19 February 2004
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Posted 19 February 2004
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Three recent articles (refs. 1, 2, and 3) have suggested that sphingolipid metabolism may be involved in the pathogenesis of Alzheimer’s disease (AD). The first one, from Xianlin Han and colleagues (1), has identified a ~threefold increase in ceramide levels in the brain of AD patients, when compared to age-matched controls. In that study, the increase in ceramide levels was accompanied by a concomitant decrease in sulfatide content in the brain, suggesting that ceramide was mainly produced by degradation of these highly abundant glycosylated forms of sphingolipids. The second article (2), from our group, has shown that cell-surface hydrolysis of sphingomyelin (SM) can regulate the rate of amyloid-β peptide (Aβ) generation via the second messenger ceramide. Finally, Sawamura and colleagues (3) have shown that sphingosine biosynthesis in the endoplasmic reticulum can also affect APP processing.
Ceramide is the backbone of all sphingolipids, including SM and glycosphingolipids (among which are the sulfatides). Glycosphingolipids are important components of myelin...
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Three recent articles (refs. 1, 2, and 3) have suggested that sphingolipid metabolism may be involved in the pathogenesis of Alzheimer’s disease (AD). The first one, from Xianlin Han and colleagues (1), has identified a ~threefold increase in ceramide levels in the brain of AD patients, when compared to age-matched controls. In that study, the increase in ceramide levels was accompanied by a concomitant decrease in sulfatide content in the brain, suggesting that ceramide was mainly produced by degradation of these highly abundant glycosylated forms of sphingolipids. The second article (2), from our group, has shown that cell-surface hydrolysis of sphingomyelin (SM) can regulate the rate of amyloid-β peptide (Aβ) generation via the second messenger ceramide. Finally, Sawamura and colleagues (3) have shown that sphingosine biosynthesis in the endoplasmic reticulum can also affect APP processing.
Ceramide is the backbone of all sphingolipids, including SM and glycosphingolipids (among which are the sulfatides). Glycosphingolipids are important components of myelin membranes and are highly enriched in white matter. SM serves both as structural component for the organization of cell membranes and as substrate for the generation of ceramide. Ceramide, in turn, when produced at the cell surface, acts as second messenger and activates several signaling events.
A new article published in the February 17 issue of PNAS by Roy Cutler and colleagues in Mark Mattson’s group (4) now extends our information by showing that aging is accompanied by specific (and not generalized) changes in ceramide/sphingolipid metabolism in the brain. The authors first analyzed sphingolipid levels in three- and 25-month-old mice, and found a specific age-related increase in two species of ceramide—the C18:0 and C24:0 isoforms. They also found increased levels of C24:0 galactosyl-ceramide. Galactosyl-ceramide serves as substrate for the biosynthesis of sulfatides and is also the first bio-product of sulfatide hydrolysis. Further hydrolysis of C24:0 galactosyl-ceramide would then liberate C24:0 ceramide. This sequence of events most likely occurs outside the cell in the white matter, is associated with loss of myelin membranes, and can explain the rise of only one isoform of ceramide. However, it remains unclear where the C18:0 isoform comes from.
After these initial results, Mark Mattson’s group analyzed different areas of AD brains and compared them to age-matched controls. Once again, they found a twofold increase in both ceramide C24:0 and galactosyl-ceramide C24:0. However, this time they also found a specific decrease of C24:0 SM. Therefore, C24:0 ceramide can originate from hydrolysis of both C24:0 sulfatides and C24:0 SM. These changes were only observed in the middle frontal gyrus (with extensive Aβ deposition and neurofibrillary tangles), but not in the cerebellum (with little or no Aβ deposits or tangles). This correlation seems to suggest that the changes are a consequence, rather than a cause, of neurodegeneration. Finally, Cutler et al. found increased lipid oxidation—once again, only in the “AD-susceptible” areas. However, when they analyzed cell membranes, they could not find any changes in SM, sulfatide, or galactosyl-ceramide levels. They only found an increase in ceramide levels, mostly C18:0 and C24:0, which correlated with the severity of the disease. These results provide the first evidence for specific changes in cell-surface ceramide in AD brains. Since the “signaling-active” ceramide is generated in the cell membrane, the above results further strengthen the possibility that this second messenger might be involved in the pathogenesis of AD. Obviously, production of ceramide from sulfatide degradation in myelin sheets may further aggravate the situation.
The second messenger, ceramide, is mostly produced by receptor-mediated activation of neutral sphingomyelinase (nSMase). However, it has long been known that oxidative stress can also activate nSMase and induce hydrolysis of cell-surface SM. This has been shown only in cell culture; direct evidence in vivo is lacking. Mark Mattson’s group tried to address this issue by analyzing lipid oxidation in AD brains and by treating primary neurons with Aβ42 (as oxidative stressor). Their results indicate that Aβ can alter ceramide/SM metabolism and induce oxidative damage in cell culture, and suggest that such events may play a role in the progression of disease. However, the definitive experiments to test/confirm such a hypothesis remain to be performed.
Throughout their paper, Cutler et al. mostly focused on ceramide and sphingolipids. However, they also analyzed cholesterol, which is strongly implicated in AD. The authors detected a constant increase in cholesterol levels in brain membranes from AD patients, which correlated with the severity of the disease. They also showed (and this is very puzzling) that Aβ itself can affect cholesterol levels in neuronal cultures, probably in association with oxidative stress, as suggested by increased levels of lipid peroxidation. However, they do not provide evidence as to whether this is due to increased biosynthesis or uptake of cholesterol. Obviously, it will be very interesting to test these possibilities in the near future. In addition to membrane cholesterol, the authors also detected changes in the levels of cholesterol esters, indicating that oxidative damage can induce profound alterations of cholesterol homeostasis and distribution in neurons. Once again, the question is: How? The answer will probably come only once we identify the intracellular determinants (lipids or proteins) that regulate cholesterol metabolism in neurons.
The results found by Cutler et al. (4) in AD brains are very similar to those the same group already published from patients with amyotrophic lateral sclerosis (5), suggesting that we are only looking at events produced by the degenerative disorder. These may be common events/alterations that occur during neurodegeneration and are induced by loss of neurons and myelin. Obviously, it is still very important to understand whether they affect the progression of the disease.
References:
1. Han X, M Holtzman D, McKeel DW Jr, Kelley J, Morris JC. Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J Neurochem. 2002 Aug;82(4):809-18.
Abstract
2. Puglielli L, Ellis BC, Saunders AJ, Kovacs DM. Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis.
J Biol Chem. 2003 May 30;278(22):19777-83. Epub 2003 Mar 20. Abstract
3. Sawamura N, Ko M, Yu W, Zou K, Hanada K, Suzuki T, Gong JS, Yanagisawa K, Michikawa M. Modulation of amyloid precursor protein cleavage by cellular sphingolipids. J Biol Chem. 2004 Jan 10 [Epub ahead of print]
Abstract
4. Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2070-5. Epub 2004 Feb 15. Abstract
5. Cutler RG, Pedersen WA, Camandola S, Rothstein JD, Mattson MP. Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis. Ann Neurol. 2002 Oct;52(4):448-57.
Abstract
View all comments by Luigi Puglielli |
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Kazuhiro Honda, George Perry, ARF Advisor (Disclosure), Mark A. Smith (Disclosure)
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Submitted 20 February 2004
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Posted 20 February 2004
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Ceramide, Cholesterol, and Oxidative Stress
In a very exciting study, Cutler and colleagues provide insight to link membrane-associated oxidative stress and neuronal degeneration in aging and Alzheimer disease (AD). Many lines of evidence suggest that oxidative stress plays a pivotal role in the pathogenesis of AD, and various views have been proposed ( Mattson, 2002; Smith et al., 2002; Butterfield, 2003). Also, as suggested by the involvement of apolipoprotein E in AD and epidemiological reports showing that treatment to lower blood cholesterol level reduces the risk of AD ( Wolozin et al., 2000), cholesterol metabolism appears to play a role in the pathophysiology of AD. Although oxidative modification of lipid has been extensively studied, a mechanism to explain the link between oxidative stress...
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Ceramide, Cholesterol, and Oxidative Stress
In a very exciting study, Cutler and colleagues provide insight to link membrane-associated oxidative stress and neuronal degeneration in aging and Alzheimer disease (AD). Many lines of evidence suggest that oxidative stress plays a pivotal role in the pathogenesis of AD, and various views have been proposed ( Mattson, 2002; Smith et al., 2002; Butterfield, 2003). Also, as suggested by the involvement of apolipoprotein E in AD and epidemiological reports showing that treatment to lower blood cholesterol level reduces the risk of AD ( Wolozin et al., 2000), cholesterol metabolism appears to play a role in the pathophysiology of AD. Although oxidative modification of lipid has been extensively studied, a mechanism to explain the link between oxidative stress and cholesterol metabolism remains largely unknown. In this regard, Cutler and colleagues demonstrate that aging itself results in increases in the amount of ceramide and related compounds. Furthermore, ceramide and related lipids accumulate in brain regions vulnerable to AD. This observation may provide an important clue to answer the question of why age-associated neuronal loss is inevitable in the senescent brain. Since the profile of various lipids extracted from AD brains is similar to that from control, neurotoxicity of amyloid-β (Aβ) might be related to the same pathways as neuronal aging.
If this is the case, how can we cope with this problem? Since ceramide would play an important role for neuronal function, manipulation of oxidative stress would seem to be a safer option. With this in mind, the authors demonstrate that α-tocopherol is effective in suppressing the increase of ceramide and HNE induced by Aβ without changing the level of sphingomyelin. While the effect of α-tocopherol on reducing the amount of ceramide is smaller than that of an inhibitor of sphingomyelin synthesis, α-tocopherol is superior in suppressing the accumulation of HNE. This study, coupled with recent reports showing the protective role of antioxidant vitamins against AD (Zandi et al., 2004), bolsters the notion that neurotoxicity induced by Aβ and oxidative stress is a fundamental determinant in senescence and AD pathophysiology.
References:
Butterfield DA. Amyloid beta-peptide [1-42]-associated free radical-induced oxidative stress and neurodegeneration in Alzheimer's disease brain: mechanisms and consequences.
Curr Med Chem. 2003 Dec;10(24):2651-9. Review. Abstract
Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2070-5. Epub 2004 Feb 15. Abstract
Mattson MP. Oxidative stress, perturbed calcium homeostasis, and immune dysfunction in Alzheimer's disease. J Neurovirol. 2002 Dec;8(6):539-50. Review. Abstract
Smith MA, Casadesus G, Joseph JA, Perry G. Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med. 2002 Nov 1;33(9):1194-9. Review.
Abstract
Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol. 2000 Oct;57(10):1439-43. Abstract
Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Norton MC, Welsh-Bohmer KA, Breitner JC; Cache County Study Group. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol. 2004 Jan;61(1):82-8. Abstract
View all comments by Kazuhiro Honda
View all comments by George Perry
View all comments by Mark A. Smith
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Timothy Tiedemann
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Submitted 26 February 2004
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Posted 1 March 2004
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Changes in brain lipid composition have been determined in 24 month-old Fischer rats compared with 6 months-old ones. The cerebral levels of sphingomyelin and cholesterol were found to be significantly increased in aged rats, whereas the amount of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid appear to be unaffected by aging. Long-term feeding with acetyl-L-carnitine was able to reduce the age-dependent increase of both sphingomyelin and cholesterol cerebral levels with no effect on the other measured phospholipids. These findings shown that changes in membrane lipid metabolism and/or composition represent one of the alterations occurring in rat brain with aging, and that long-term feeding with acetyl-L-carnitine can be useful in normalizing these age-dependent disturbances.
Reference:
Aureli T, Di Cocco ME, Capuani G, Ricciolini R, Manetti C, Miccheli A, Conti F. Effect of long-term feeding with acetyl-L-carnitine on the age-related changes in rat brain lipid composition: a study by 31P NMR...
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Changes in brain lipid composition have been determined in 24 month-old Fischer rats compared with 6 months-old ones. The cerebral levels of sphingomyelin and cholesterol were found to be significantly increased in aged rats, whereas the amount of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid appear to be unaffected by aging. Long-term feeding with acetyl-L-carnitine was able to reduce the age-dependent increase of both sphingomyelin and cholesterol cerebral levels with no effect on the other measured phospholipids. These findings shown that changes in membrane lipid metabolism and/or composition represent one of the alterations occurring in rat brain with aging, and that long-term feeding with acetyl-L-carnitine can be useful in normalizing these age-dependent disturbances.
Reference:
Aureli T, Di Cocco ME, Capuani G, Ricciolini R, Manetti C, Miccheli A, Conti F. Effect of long-term feeding with acetyl-L-carnitine on the age-related changes in rat brain lipid composition: a study by 31P NMR spectroscopy.
Neurochem Res. 2000 Mar;25(3):395-9. Abstract
References:
View all comments by Timothy Tiedemann |
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Yusuf Hannun, lina obeid
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Submitted 2 March 2004
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Posted 2 March 2004
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The study by Cutler et al. reports on increases in the levels of the lipids ceramide and cholesterol in the aging brain. These changes are further exacerbated in Alzheimer’s disease (AD) brains, which also show decreased levels of sphingomyelin (a precursor/product to ceramide). Notably, these changes are accompanied by increased lipid oxidation products, and they were manifest in the middle frontal gyrus (an area highly affected in AD) but not in cerebellum (which demonstrated modest disease changes). Moreover, the increases in ceramide correlated with the severity of the disease.
Given the known roles of ceramide in stress responses and in mediating cytotoxic responses, the authors then exposed hippocampal neurons (in primary culture) to amyloid-β peptide (Aβ), and found that Aβ induced oxidation of membrane lipids and accumulation of ceramide and cholesterol. The authors then implicate the accumulated ceramide in mediating the toxicity of Aβ by demonstrating that an inhibitor of ceramide synthesis (ISP-1/myriocin) inhibited cell death. Using inhibitors...
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The study by Cutler et al. reports on increases in the levels of the lipids ceramide and cholesterol in the aging brain. These changes are further exacerbated in Alzheimer’s disease (AD) brains, which also show decreased levels of sphingomyelin (a precursor/product to ceramide). Notably, these changes are accompanied by increased lipid oxidation products, and they were manifest in the middle frontal gyrus (an area highly affected in AD) but not in cerebellum (which demonstrated modest disease changes). Moreover, the increases in ceramide correlated with the severity of the disease.
Given the known roles of ceramide in stress responses and in mediating cytotoxic responses, the authors then exposed hippocampal neurons (in primary culture) to amyloid-β peptide (Aβ), and found that Aβ induced oxidation of membrane lipids and accumulation of ceramide and cholesterol. The authors then implicate the accumulated ceramide in mediating the toxicity of Aβ by demonstrating that an inhibitor of ceramide synthesis (ISP-1/myriocin) inhibited cell death. Using inhibitors of oxidation (a-tocopherol) and inducers of oxidative stress (HNE), they order the cytotoxic pathway such that Aβ incites an oxidative stress followed by ceramide accumulation, which then mediates cytotoxicity.
Another recent study on the role of ceramide in mediating oligodendrocyte death in response to Aβ reached similar conclusions and provided further evidence for activation of neutral sphingomyelinase as the key step responsive to the action of Aβ and the attendant oxidative stress (Lee et al., 2004). A recent in-vivo study demonstrated that intracerebral injection of Aβ induced lipid peroxidation, which was responsible for activation of neutral sphingomyelinase and a significant and prolonged increase in the levels of ceramide (Alessenko et al., 2004).
Together, these results provide significant evidence for the operation of an oxidation/ceramide-based mechanism of stress response in aging brain and AD. For investigators studying AD, this mechanism begins to bring together previously known correlates and players invoked in the pathogenesis of this disorder, including the cytotoxic actions of Aβ, the increased oxidative stress and load of oxidative injury in aging and AD brain, the previously noted increases in ceramide levels in AD brain (e.g., Han et al., 2002), the established roles of sphingolipids in mediating and regulating stress responses, and the noted roles of ceramide in neuronal apoptosis (e.g., Puranam et al., 1999).
What is most remarkable and gratifying to those of us who have been studying bioactive lipids are the current rewards in translating basic research in this field to establishing the roles of these molecules in human disease. Indeed, this study illustrates how the development of basic research now allows significant and likely predictions. In the case of ceramide, multiple studies had established its roles and participation in various apoptotic responses and the ability of inhibitors of ceramide formation to ameliorate cytotoxic responses. Mechanistic studies had disclosed that oxidative stimuli indirectly activate neutral sphingomyelinase leading to the generation of ceramide; this prompted the proposal that ceramide provides a molecular link in transducing cell responses to oxidative stress.
Obviously, more mechanistic insight is required. For example, how does oxidation activate sphingomyelinase? How does ceramide transduce cytotoxic effects of stimuli such as Aβ? At the same time, it is now clear that pursuing the oxidation/sphingolipid connection promises novel insight as well as the possibilities of specific therapeutics for AD, for example, inhibitors of neutral sphingomyelinase.
View all comments by Yusuf Hannun
View all comments by lina obeid |
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Alexei R. Koudinov
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Submitted 21 February 2004
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Posted 2 March 2004
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Fats, Amyloid-β, Oxidative Stress: Restoring Neuronal Function?
We read with interest this article, news summary, and the responses by knowledgeable commentators. Preliminary and related findings were presented by authors at the Society for Neuroscience Annual Meeting 2002 (Abstract
#884.10) and 2003 (Abstract
#406.7).
We are very glad that authors experimentally added to our findings that there are complex biochemical relations among Aβ, cholesterol, phospholipids, oxidative stress, and neuronal function. A few years ago, we were the first to show that Aβ modulates neural lipid synthesis (in PC12 cells, in primary cerebral cell cultures, in utero in rat fetuses, and ex vivo in hippocampal and cortical slices), and that oxidative stress reverses the stimulatory effect of the peptide. We explain such interrelation in functional,
not pathological terms....
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Fats, Amyloid-β, Oxidative Stress: Restoring Neuronal Function?
We read with interest this article, news summary, and the responses by knowledgeable commentators. Preliminary and related findings were presented by authors at the Society for Neuroscience Annual Meeting 2002 (Abstract
#884.10) and 2003 (Abstract
#406.7).
We are very glad that authors experimentally added to our findings that there are complex biochemical relations among Aβ, cholesterol, phospholipids, oxidative stress, and neuronal function. A few years ago, we were the first to show that Aβ modulates neural lipid synthesis (in PC12 cells, in primary cerebral cell cultures, in utero in rat fetuses, and ex vivo in hippocampal and cortical slices), and that oxidative stress reverses the stimulatory effect of the peptide. We explain such interrelation in functional,
not pathological terms. We also are intrigued by the PNAS article proposal of "a sequence of events in the pathogenesis of AD in which Aβ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease."
Alzheimer's changes in neurochemistry of Aβ and oxidative stress represent physiological transitory mechanisms aiming to compensate impaired dynamics of cholesterol and other lipid components of neural membranes that we believe are primary causes of neurotransmission and synaptic plasticity failure in Alzheimer's patients.
Therefore, in contrast to the reasoning of Cutler et al., we earlier proposed that Aβ and oxidative stress modulation are integrated compensatory factors that help cure the neural plasticity impaired by lipid metabolism break. This is because the oxidative stress cascade affects membrane fluidity and itself is critical for synaptic function and plasticity (as shown by others) and because
Aβ may improve synaptic plasticity by modulating neural cholesterol dynamics.
Moreover, a further link could be drawn based on the observation of antioxidant properties of Aβ under physiological conditions. Thus, the slow-onset component of the long-term potentiation (LTP) can be pharmacologically induced by Aα-tocopherol (vitamin E) and Aβ; it is impaired in the transgenic mice overexpressing enzyme Cu/Zn superoxide dismutase (SOD-1), and may be attributed to the lipid antioxidant modulation by vitamin E or Aβ, and
dependency of slow LTP component on a unique molecular mechanism.
In summary, we appreciate this fascinating report. We would like to encourage others to join the research linking lipids, oxidative stress, and neurodegeneration.
References:
Koudinov AR, Koudinova NV. Amyloid beta protein restores hippocampal long term potentiation: A central role for cholesterol? Neurobiol Lipids, 15 Sept 2003. 1, 8. Full text.
View all comments by Alexei R. Koudinov
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Timothy Tiedemann
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Submitted 4 March 2004
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Posted 4 March 2004
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Acetyl-L-Carnitine has shown some efficacy in treating early onset AD in some small, short term trials on several parameters of memory and in one as an adjuvant therapy in combination with acetylcholinesterase inhibitors.
References:
Bianchetti A,Rozzini R,Troibucchi M, Effects of Acetyl-L-Carnitine in Alzheimer's patients unresponsive to acetylcholinesterase inhibitors.
Curr Med Res Opin 2003,19(6)350-3. Abstract
Montgomery SA,Thal LJ,Amrein R, Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease. Int Clin Psychopharmacol 2003 Mar;18(2):61-71. Abstract
Brooks JG 3rd,Yesavage JA, Carta A,Bravi D. Acetyl-L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double blind, placebo-controlled study using the trilinear approach. Int Psychogeriatrics 1998 Jun;10(2)193-202....
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Acetyl-L-Carnitine has shown some efficacy in treating early onset AD in some small, short term trials on several parameters of memory and in one as an adjuvant therapy in combination with acetylcholinesterase inhibitors.
References:
Bianchetti A,Rozzini R,Troibucchi M, Effects of Acetyl-L-Carnitine in Alzheimer's patients unresponsive to acetylcholinesterase inhibitors.
Curr Med Res Opin 2003,19(6)350-3. Abstract
Montgomery SA,Thal LJ,Amrein R, Meta-analysis of double blind randomized controlled clinical trials of acetyl-L-carnitine versus placebo in the treatment of mild cognitive impairment and mild Alzheimer's disease. Int Clin Psychopharmacol 2003 Mar;18(2):61-71. Abstract
Brooks JG 3rd,Yesavage JA, Carta A,Bravi D. Acetyl-L-carnitine slows decline in younger patients with Alzheimer's disease: a reanalysis of a double blind, placebo-controlled study using the trilinear approach. Int Psychogeriatrics 1998 Jun;10(2)193-202. Abstract
Bigini P, Larini S, Pasquali C, Muzio V, Mennini T. Acetyl-L-carnitine shows neuroprotective and neurotrophic activity in primary culture of rat embryo motorneurons, Neurosci Letter 2002 Sep 6;329(3):334-8. Abstract
View all comments by Timothy Tiedemann |
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Related News: Fats, Aβ, Oxidative Stress: Feeding Forward and Backward, Killing Neurons?
Comment by: Jacob Mack
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Submitted 26 August 2005
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Posted 30 August 2005
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I recommend the Primary Papers
Superb paper! I think linking this research with receptor-dependent and -independent pathways (CB1 receptors) (arachidonic acid, anadamide) will present an insightful link between lipids, cholesterol, various esters, and signal transduction via neuronal cell membranes. It might also elucidate mechanisms of AD pathogenesis and new treatment options, for example, cannabinoid manipulation of lipid levels or modulation of intracellular cholesterol production through nanogene therapy. Great insights in this paper. View all comments by Jacob Mack |
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