What’s good for the heart may be good for the brain. Apolipoprotein A-I is the major component of high-density lipoprotein (HDL, or “good cholesterol”) in the blood, and is under intensive investigation by cardiovascular researchers for its ability to protect against heart disease. New evidence suggests that it might also help defend the brain against the cognitive deficits associated with Alzheimer’s-like pathology. In the September 16 issue of Journal of Biological Chemistry online, researchers led by Ling Li at the University of Alabama at Birmingham (now at the University of Minnesota in Minneapolis) report that overexpressing ApoA1 in a mouse model of AD protects the mice from cognitive deficits and curtails buildup of amyloid in brain blood vessels. Conversely, in an independent study published in the August 25 issue of Journal of Biological Chemistry online, researchers led by Radosveta Koldamova at the University of Pittsburgh in Pennsylvania found that AD mouse models that lack ApoA1 fare poorly on cognitive tests and deposit more Aβ in cerebral blood vessels than do AD mice with ApoA1. Together these papers add to the evidence that ApoA1 may help protect brain health, and suggest interventions that raise ApoA1 levels as potential future therapeutics for AD.

Previous research on the relationship between ApoA1 and AD has been inconsistent. Some studies have shown that low levels of ApoA1 are correlated with more severe AD, and high levels of ApoA1 with a lower risk of AD (see Merched et al., 2000; Saczynski et al., 2007; Bates et al., 2009). Other studies, however, have found no connection between ApoA1 and AD risk (see Song et al., 1997 and Reitz et al., 2004), or even a reverse association, with high HDL correlated with increased neurofibrillary tangles (see Launer et al., 2001 ). On the genetic front, one positive and one negative study have been published to date, see ApoA-1 gene overview on AlzGene.

Other studies have hinted at a cognitive effect. High HDL levels associate with sharper mental abilities in the elderly (see ARF related news story on Barzilai et al., 2006), while low HDL levels are a risk factor for memory decline in middle-aged adults (see Singh-Manoux et al., 2008). What might be behind these apparent benefits? ApoA1 is known to have anti-inflammatory effects, and indeed, in a mouse model of brain inflammation, an ApoA1 mimetic improved cognitive deficits (see Buga et al., 2006). ApoA1 has also been shown in-vitro to directly inhibit the aggregation of Aβ, suggesting it could lessen plaque formation (see Koldamova et al., 2001). Surprisingly, however, when researchers led by David Holtzman at Washington University in St. Louis, Missouri, crossed an AD mouse model with an ApoA1 null mouse, they saw no change in amyloid deposition in the brain (see Fagan et al., 2004).

To try to clarify the ApoA1 picture, first author Terry Lewis and colleagues from the University of Alabama group used an overexpression strategy, crossing AD mice transgenic for APP and PS1 mutations (APPswe/PSEN1ΔE9) with mice that expressed human ApoA1. The triple transgenic mice showed no difference in Aβ deposition in brain tissue compared to APP/PS1 mice, in agreement with the results of Holtzman and colleagues. However, in brain blood vessels the triple transgenics had about half the plaque load of the AD mice, suggesting that ApoA1 is protective. Lewis and colleagues also showed that the triple transgenics had less neuroinflammation, including less microglial and astrocyte activation. The most intriguing results were cognitive, however. At 10 months of age, the AD mice showed learning and memory defects in the Morris water maze, but the triple transgenics continued to perform as well as wild-type mice. The triple transgenics also performed better than the APP/PS1 mice in a memory retention test.

The results from this ApoA1 gain-of-function study dovetail with the loss-of-function findings from the University of Pittsburgh group. First author Iliya Lefterov crossed APP/PS1 mice to ApoA1 knockout mice, and likewise found that the triple transgenics showed no change in amyloid plaques in the brain tissue at 12 months of age, nor did they have differences in the levels of Aβ oligomers in the brain or in APP processing. However, compared to APP/PS1 mice, the brain blood vessels of the triple transgenics were far more clogged with amyloid plaque, showing a ten-fold increase in insoluble Aβ40 and a slight increase in Aβ42. Lefterov and colleagues also found cognitive defects in the mice lacking ApoA1, with triple transgenics performing worse on tests of spatial learning and memory retention than did APP/PS1 mice.

A strength of these papers, Holtzman said, is that even though the studies were performed independently and use different approaches, the results are consistent. He added that together the papers “indicate that HDL biology is important in aspects of Alzheimer’s pathology, and perhaps even in brain function.” Holtzman points out that the major component of brain HDL is ApoE, the strongest genetic risk factor for non-familial AD. Another brain HDL, ApoJ (also known as clusterin), ranks number 2 in the AlzGene Top Results. One difference between these cholesterols is that unlike ApoE and ApoJ, ApoA1 is not made in the brain; its concentration is much higher in blood, but enough ApoA1 crosses the blood-brain barrier to give it a presence in brain as well.

The next question, Holtzman suggested, is to find out how ApoA1 is improving memory. Is it protecting memory by preventing cerebral amyloid buildup, or can ApoA1 directly affect neurons and synapses in the brain?

Li and colleagues would like to know this too. To investigate whether the cholesterol can have a direct synaptic effect, Li said, they will compare the electrophysiology of slice cultures in the presence and absence of ApoA1. Another possibility, Li speculated, is that ApoA1 preserves memory by decreasing neuroinflammation. A third option is that amyloid deposits in cerebral blood vessels could harm brain function by decreasing the flow of nutrients into the brain, or by slowing Aβ clearance out of the brain, she said, adding that blood vessel amyloid burden also increases the risk of a cerebral hemorrhage.

Once they understand better how ApoA1 acts in the brain, Li said, the ultimate goal will be to move from animal studies to humans and see if the same relationship holds. Eventually, methods for raising ApoA1 could be evaluated in clinical trials to see if they protect against memory loss in AD. People can already increase their HDL, and therefore ApoA1, by exercise, a heart-healthy diet, and the vitamin niacin, Li said. In addition, new HDL-raising drugs may come out of the cardiovascular clinical research field.

Koldamova and colleagues are interested in analyzing their triple transgenic ApoA1 knockout mice at earlier ages. At 12 months, the AD mice are at the peak of Aβ deposition, which may be why the loss of ApoA1 produced no visible increase in accumulation, Koldamova said. She speculated that in younger mice, the researchers might see higher levels of Aβ oligomers in the brain tissue of the knockouts, either due to decreased clearance from brain, or due to the loss of ApoA1’s inhibitory effect on aggregation. They will also look for behavior and memory deficits at earlier ages, Koldamova said.

Yet another avenue will be to explore the role of ABCA1, the master regulator of cholesterol efflux from cells, Lefterov said. ABCA1 controls both ApoE and ApoA1, and knockouts of ABCA1 have been shown to increase amyloid deposition (see ARF related news story on Koldamova et al., 2005). “The connection between ApoE and ApoA1 might well be ABCA1, or even the master transcriptional regulator of all three guys, Liver X Receptor,” Lefterov said. He plans to examine transgenic mice that express human familial loss-of-function variants of ABCA1 for changes in ApoE and ApoA1.

Compared to its more famous cousins ApoE and ApoJ, ApoA1 has been largely overlooked till now in brain health, Koldamova said, but the new research suggests it might play an important role in AD and have therapeutic potential. “I hope [these results] will turn more attention on ApoA1.”—Madolyn Bowman Rogers

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. These are an interesting set of papers, from two independent groups, that demonstrate the protective effect of ApoA-I against certain aspects of Aβ pathology in APP/PS1 transgenic mice. In the first paper by Lefterov et al. the authors took the approach of crossing APP/PS1 mice with ApoA-I KO mice and showed that this exacerbated the behavioral deficits of APP/PS1 mice. Most notably, the authors found that although the absence of ApoA-I had no effect on total brain Aβ levels, soluble Aβ oligomers, or parenchymal Aβ plaque load, there was a marked increase in cerebral amyloid angiopathy (CAA).

    The second paper by Lewis et al. took the opposite approach of breeding APP/PS1 mice with transgenic mice expressing human ApoA-I. There, studies found the opposite result where the triple transgenic mice had improved behavioral performance and decreased levels of CAA. Furthermore, this study went on to show that in the presence of ApoA-I there was a decrease in glial activation and pro-inflammatory cytokine production. Together, these studies further suggest that in addition to its well-known cardiovascular effects, ApoA-I may also have profound effects in the CNS that may be important in the pathogenesis of AD.

    On another point, I was particularly intrigued with how these two papers further support the concept studied in my lab, i.e. the relationship between CAA, neuroinflammation, and cognitive impairment. Earlier, we reported that cerebral microvascular amyloid deposition promotes neuroinflammation and behavioral deficits in the vasculotropic mutant APP mouse model Tg-SwDI (1,2). Reducing microvascular CAA in Tg-SwDI diminished the associated neuroinflammation, and this occurred in the absence of any changes in total Aβ load or the levels of soluble Aß oligomers (3).

    This earlier finding is consistent with the present results of Lefterov et al. that show in the absence of ApoA-I worsening behavioral performance in the APP/PS1 mice was associated with increased CAA load, not the level of soluble Aβ oligomers. Moreover, specifically reducing CAA-induced microglial activation improved behavioral performance in Tg-SwDI mice further strengthening the link between CAA, neuroinflammation, and cognitive impairment (4).

    These two papers indicate that ApoA-I fits as a protein that may be more specifically tailored towards the cerebral vascular contribution of AD and related disorders. First, Lefterov et al. show that ApoA-I hinders Aβ assembly into larger oligomeric/fibrillar structures and blocks their toxicity towards cultured human brain vascular smooth muscle cells. Proper assembly of Aβ is required for brain vascular smooth muscle cell toxicity (5,6). Second, ApoA-I may be intimately involved with efficient efflux of Aβ out of brain across the cerebral vasculature. Therefore, as the present two papers suggest, increasing or decreasing the expression of ApoA-I may have profound effects on the ability to clear Aβ at the level of cerebral blood vessel influencing the development of CAA. It would be interesting to determine what the plasma levels of Aβ are in these models with altered ApoA-I expression.

    Finally, the anti-inflammatory properties of ApoA-I may directly suppress localized CAA-induced neuroinflammation. In any case, these two manuscripts support further investigation into the specific contribution of CAA to neuroinflammation and cognitive impairment and how endogenous molecules, such as ApoA-I, may influence these processes.

    References:

    . Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005 Aug;167(2):505-15. PubMed.

    . Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice. Neuroscience. 2007 Apr 25;146(1):98-107. Epub 2007 Feb 28 PubMed.

    . Reducing cerebral microvascular amyloid-beta protein deposition diminishes regional neuroinflammation in vasculotropic mutant amyloid precursor protein transgenic mice. J Neurosci. 2005 Jul 6;25(27):6271-7. PubMed.

    . Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci. 2007 Mar 21;27(12):3057-63. PubMed.

    . Pathologic amyloid beta-protein cell surface fibril assembly on cultured human cerebrovascular smooth muscle cells. J Neurochem. 1998 Jan;70(1):216-23. PubMed.

    . Disruption of pathologic amyloid beta-protein fibril assembly on the surface of cultured human cerebrovascular smooth muscle cells. Amyloid. 2001 Jul;8 Suppl 1:20-7. PubMed.

  2. There is now substantial evidence that the accumulation of soluble and insoluble amyloid beta (Aβ) in the brain is a major factor in the etiology of AD. Preventing the accumulation of Aβ in the brain or facilitating its removal has become a major therapeutic goal for Alzheimer’s disease. Aβ-immunotherapy removes insoluble plaques of Aβ from the brain, but it appears that Aβ becomes entrapped in the perivascular drainage pathways by which a proportion of the Aβ is normally eliminated and results in increased severity of cerebral amyloid angiopathy (CAA). In addition, levels of soluble Aβ in the brain rise as a further indication that immunotherapy does not result in the complete elimination of Aβ from the brain. This has emphasized the importance of the perivascular drainage routes in the elimination of Aβ from the brain.

    The major impact of the experimental work published by Iliya Lefterov et al. is that it represents a step towards elucidating the role of major risk factors such as hypercholesterolemia and apolipoproteins in impeding the elimination of Aβ from the AD brain. Lipidated and non-lipidated ApoA-I inhibit the aggregation and toxicity of both Aβ 40 and 42. Deletion of the mouse ApoA-I gene significantly worsened cognitive performance in APP/PS1 transgenic mice, but did not change the total Aβ load. The important aspect is that arterial CAA was increased. The authors suggest that this may be due to the formation of Aβ fibrils in the vicinity of blood vessels and/or the effect that ApoA-I has on the smooth muscle cells. However, this does not explain the 5:1 ratio of Aβ40:42 observed in the APP/PS1ΔE9/ApoA-Iko mice. We suggest that ApoA-I may act as a chaperone, facilitating the transport of Aβ along the basement membranes of cerebral arteries. The absence of ApoA-I may result in a disruption to the normal dynamics of perivascular drainage, resulting in the accumulation of Aβ in the walls of arteries.

    The paper authored by Terry Lewis et al. describes high levels of HDL accompanied by unaltered levels of Aβ load, improved cognitive function and reduced neuroinflammation in the brains of APP/PS1 transgenic mice crossed with ApoA-I human replacement gene mice, compared to transgenic APP/PS1 mice. Overexpression of ApoA-I led to a reduction in CAA, although we do have concerns about using a non-specific dye (Congo red) as a sole marker for the amyloid deposition associated with blood vessels. These results suggest that ApoA-I facilitates the elimination of Aβ along the basement membranes of cerebral capillaries and arteries, but the overproduction of mutant Aβ in the extracellular spaces of the brain parenchyma leads to the formation of plaques and a rise in soluble Aβ.

    The roles that ApoA and ApoE may have in the dynamics of perivascular drainage and clearance of Aβ from the brain remain to be explored.

References

News Citations

  1. Long-Lived and Sharp Through "Good" Cholesterol?
  2. ABCA1 Loss Lowers ApoE, Not Amyloid; New ApoE Immunology

Paper Citations

  1. . Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer's disease. Neurobiol Aging. 2000 Jan-Feb;21(1):27-30. PubMed.
  2. . The relation between apolipoprotein A-I and dementia: the Honolulu-Asia aging study. Am J Epidemiol. 2007 May 1;165(9):985-92. PubMed.
  3. . Association of cardiovascular factors and Alzheimer's disease plasma amyloid-beta protein in subjective memory complainers. J Alzheimers Dis. 2009;17(2):305-18. PubMed.
  4. . Cerebrospinal fluid apo E and apo A-I concentrations in early- and late-onset Alzheimer's disease. Neurosci Lett. 1997 Aug 15;231(3):175-8. PubMed.
  5. . Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol. 2004 May;61(5):705-14. PubMed.
  6. . Cholesterol and neuropathologic markers of AD: a population-based autopsy study. Neurology. 2001 Oct 23;57(8):1447-52. PubMed.
  7. . A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology. 2006 Dec 26;67(12):2170-5. PubMed.
  8. . Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife: the Whitehall II study. Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1556-62. PubMed.
  9. . D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet. J Lipid Res. 2006 Oct;47(10):2148-60. PubMed.
  10. . Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. Biochemistry. 2001 Mar 27;40(12):3553-60. PubMed.
  11. . ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis. Am J Pathol. 2004 Oct;165(4):1413-22. PubMed.
  12. . Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005 Dec 30;280(52):43224-35. PubMed.

External Citations

  1. ApoA-1 gene overview
  2. APPswe/PSEN1ΔE9
  3. AlzGene Top Results

Further Reading

Papers

  1. . Low HDL cholesterol is a risk factor for deficit and decline in memory in midlife: the Whitehall II study. Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1556-62. PubMed.
  2. . Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer's disease. Neurobiol Aging. 2000 Jan-Feb;21(1):27-30. PubMed.
  3. . The relation between apolipoprotein A-I and dementia: the Honolulu-Asia aging study. Am J Epidemiol. 2007 May 1;165(9):985-92. PubMed.
  4. . Association of cardiovascular factors and Alzheimer's disease plasma amyloid-beta protein in subjective memory complainers. J Alzheimers Dis. 2009;17(2):305-18. PubMed.
  5. . Cerebrospinal fluid apo E and apo A-I concentrations in early- and late-onset Alzheimer's disease. Neurosci Lett. 1997 Aug 15;231(3):175-8. PubMed.
  6. . Relation of plasma lipids to Alzheimer disease and vascular dementia. Arch Neurol. 2004 May;61(5):705-14. PubMed.
  7. . Cholesterol and neuropathologic markers of AD: a population-based autopsy study. Neurology. 2001 Oct 23;57(8):1447-52. PubMed.
  8. . A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology. 2006 Dec 26;67(12):2170-5. PubMed.
  9. . D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet. J Lipid Res. 2006 Oct;47(10):2148-60. PubMed.
  10. . Apolipoprotein A-I directly interacts with amyloid precursor protein and inhibits A beta aggregation and toxicity. Biochemistry. 2001 Mar 27;40(12):3553-60. PubMed.
  11. . ApoAI deficiency results in marked reductions in plasma cholesterol but no alterations in amyloid-beta pathology in a mouse model of Alzheimer's disease-like cerebral amyloidosis. Am J Pathol. 2004 Oct;165(4):1413-22. PubMed.
  12. . Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005 Dec 30;280(52):43224-35. PubMed.

Primary Papers

  1. . Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. J Biol Chem. 2010 Nov 19;285(47):36958-68. PubMed.
  2. . Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice. J Biol Chem. 2010 Nov 19;285(47):36945-57. PubMed.