Sheng JG, Price DL, Koliatsos VE.
Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Abeta amyloidosis.
J Neurosci. 2002 Nov 15;22(22):9794-9.
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These papers provide exciting new evidence that plaque formation can occur from axonally transported APP/Aβ. Both investigations unilaterally lesioned the perforant pathway of plaque-bearing APP Swedish/PS1DE9 mice and found markedly reduced amyloid plaque burden one month postlesion in the ipsilateral hippocampus, especially in the molecular layer of the dentate gyrus. The Lazarov et al. study, with the less ideal title, additionally demonstrated provocative evidence that preplaque unilaterally lesioned mice do not have differences in hippocampal plaque burden when they were sacrificed four months post-lesion. However, both studies are consistent with our recent study demonstrating that Aβ accumulation and plaque formation occurs within neuronal processes/synaptic compartments.
Tangles Come before Plaques on the Perforant Pathway
The one system where transport of APP and its relationship to amyloid deposition has now been well-established is the perforant pathway. Hyman and colleagues (Hyman et al., 1986; Hyman et al., 1988) pointed out some years ago that this pathway was one of the earliest affected in Alzheimer's disease, with the evidence based largely on the presence of tau abnormalities and tangles in the entorhinal cortex neurons projecting to the hippocampus. The studies of Hyman and of Braak and colleagues (Braak et al., 1991) make clear that at least in this pathway, tau pathology in entorhinal neurons precedes amyloid deposition in the terminal fields, and it is tempting to speculate that at least in this one case, abnormalities of APP processing, and deposition of beta amyloid in the terminal fields may be a result from the formation of tangles in the cell bodies. I wonder how often this might be the case in AD.
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A direct demonstration of the perforant pathway terminal zone in Alzheimer's disease using the monoclonal antibody Alz-50.
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The two studies demonstrate that if you interrupt the supply of APP to terminals in cortical brain circuits, you abort even existing amyloid deposits outside neurons. This shows that you need a constant supply of APP to maintain the plaques, or that structural changes in the brain that follow these manipulations (what we call "plasticity") disrupt, in biochemical or even physical fashion, the microenvironment of the brain neuropil enough to "break" the plaque deposits. We used a model different from Sam and his colleagues, simply because I did not like the Scouten knife when I used it in the past, but the results are very similar.
The two studies also have slightly different emphases; we focused more on the hippocampal microanatomy, whereas Sam and his colleagues focused more on a time course of events. I am also a bit more conservative in the interpretation of findings. I believe we cannot draw conclusions on why this very interesting phenomenon happens, and that the two interpretations set up above (i.e., dynamic balance between buildup and cleansing versus plasticity of the brain) are equally compelling. I am not sure about the role of glia in this. The time course does not eliminate our need to consider plasticity factors, especially considering that the longest survival times used in the study of Sam et al. represent one-fifth to one-sixth of the life span of these mice. In fact, I am especially excited by the fact that synaptic changes may be at play, and Jin Sheng and I are planning the next wave of experiments to exploit precisely these factors. This may open up novel possibilities in dealing with amyloid deposits without having to go through immunological manipulations that may carry too much of a clinical risk.
See a BIG picture
I read with great interest the article by Lazarov et al. As the authors state, they set "to examine whether APP transported via the perforant pathway is a major contributor to accumulation of Aβ deposits in the hippocampus." They "performed unilateral lesions of the perforant pathway of transgenic mice which express both the FAD-linked human PS1-E9 variant and a chimeric mouse-human APP Swedish (APPswe) and assessed amyloid burden in the hippocampal formation after the lesion." They further concluded that the "findings are consistent with the compelling in vivo demonstrations that, in diffuse plaques of AD patients and aged nonhuman primates, Aβ is present along neuronal dendrites and around the soma of neurons included in the plaques."
It is important to notice that the article misses the Congo red (or thioflavin) staining for plaque-like amyloid, and largely relies on the 6E10 antibody that recognizes just the human sequence of Aβ protein. Two unresolved issues are: How would the rodent’s own APP and Aβ behave under the experimental condition of perforant pathway lesioning? What would happen in wild-type animals with no transgene present? The latter experimental condition would likely match the one observed by the authors in the last set of the experiments when they "performed unilateral perforant pathway lesions in transgenic mice at four months of age, a time at which amyloid deposition is still undetectable." Four months later, brain sections showed no difference in the amyloid immunohistochemistry. However, there is no data for Aβ at a time less than one month after lesioning (when one would expect the changes to occur in these animals).
The genetically naive animals (which authors did not report on or discuss) would better represent human physiology, would not express a severe amyloid burden (a characteristic of the used APP transgenics that is irrelevant to the gradual slow onset of the most common sporadic form of Alzheimer’s), but could well have a reactive increase in amyloid staining after the lesioning.
This possibility is well-supported by a related article published a year ago1 that deals with the "alterations in ApoE and ApoJ in relation to degeneration and regeneration in a mouse model of entorhinal cortex lesion." Its results "indicate that ApoE and ApoJ are upregulated after injury and parallel clearance of cholesterol and lipid debris from the site of injury. This coordinated alteration in apolipoproteins may redistribute lipid material to sprouting fibers to promote neurite extension, and may play an important role in long-term plasticity changes following injury."1 Like Aβ, ApoE and ApoJ colocalize to an Alzheimer's plaque.
It is important to note that soluble Aβ is itself an apolipoprotein of the lipoproteins in the circulation and in the CNS. As an apolipoprotein. Aβ affects membrane lipid dynamics (see Ref. 2 for detailed bibliography). Particularly, Aβ modulates neuronal cholesterol esterification, influx, and efflux, and thus may regulate intracellular compartmentation and extracellular trafficking of neural cholesterol. Aβ also modulates the physical property of neuronal membrane fluidity, which is important for receptor function. Additionally, Aβ increases neural membrane lipid synthesis, in contrast to the peptide inhibitory effect, observed in human hepatic HepG2 and in HEK293 cells, in fetal rat liver and in neuronal tissue under the condition of potassium-evoked depolarization and under oxidative stress.(3,4,5) The latter data highlight the importance of developmental, tissue, and neuronal functional specificity of the relationship between Aβ and membrane lipid biochemistry, which may vary in different brain regions and be of special importance in determining Alzheimer's specific areas of neurodegeneration as well as for interpretation of the above article. The above explains why Aβ may well follow the metabolic and functional fate described for ApoE and ApoJ.
Other than lesioning (which yields the neural repair), an increased activity-dependent plasticity burden also imposes the need for membrane rearrangements and synaptogenesis(6,7) (see AlzForum neuroplasticity live discussion). Such a normal condition may mimic the increased demand for membrane dynamics and require an increase in neurons of Aβ, ApoE, and ApoJ.
In fact, Lazarov et al. state that they "cannot rule out the possibility that Aβ production-secretion and subsequent deposition at terminal fields of entorhinal afferents might be a function of synaptic activity-dependent release of Aβ from dendritic spines of dentate granule cells."
However, they undercite the conclusion of their past contribution that "Aβ secretion may normally function as a negative feedback to control synaptic function."8 The latter is supported by a number of observations, particularly by their own observation of neuronal activity-dependent secretion of natural Aβ,8 by an increase of synaptic amyloid precursor protein with learning capacity in rats,9 by upregulation of a synaptic vesicle protein transcript by Aβ1-42,10 and the amyloid precursor protein increase with development.11 The modulation of APP processing that yields Aβ by several neurotransmission systems (including cholinergic,(12,13) serotoninergic,14 and glutamatergic15) leaves little doubt regarding the vital necessity of the APP/Aβ physiology and chemistry for synaptic function.16 For further details on the role for APP/Aβ in neural function and synaptic plasticity, please see our related commentary on Pfeifer et al. (15 November 2002).
In my view, the take-home message of the important study by Lazarov et al. is a call on the neuroscience community to characterize the normal function of APP and Aβ at the synapse. The conclusion in a comment that the Lazarov study et al. provides "exciting new evidence that plaque formation can occur from axonally transported APP/Aβ" was actually not in itself tested in this study.
Koudinov AR, Koudinova NV. Brain cholesterol pathology is the cause of Alzheimer's disease. Clin Med Health Res. published online November 27, 2001, clinmed/2001100005. Abstract
A.Koudinov. Failure of neural cholesterol dynamics is a primary pathogenic event in sporadic Alzheimer's disease. Comment. AlzForum online discussion: Cholesterol and Alzheimer's-Charging Fast but Still at a Distance From Solid Answers. Posted 15 Nov. 2002. Abstract
Kamenetz FR, Tomita T, Borchelt DR, Sisodia SS, Iwatsubo T, Malinow R. Activity dependent secretion of b-amyloid: roles of b -amyloid in synaptic transmission. Soc Neurosci Abstr. 26, 491 (2000). Abstract
12. Von Der Kammer H., et al. Regulation of Gene Expression by Muscarinic Acetylcholine Receptors: A Comprehensive Approach for the Identification of Regulated Genes. Ann. N.Y. Acad. Sci., December 1, 2000; 920(1): 305–308. Abstract
13. Isacson O, Lin I. Cholinergic Modulation of Amyloid Processing and Dementia in Animal Models of Alzheimer's Disease. Ann. N.Y. Acad. Sci., December 1, 2000; 920(1): 309 - 314. Abstract
14. Nitsch RM, Deng M, Growdon JH, Wurtman RJ. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J Biol Chem. 1996 Feb 23;271(8):4188-94. Abstract
15. Nitsch RM, Deng A, Wurtman RJ, Growdon JH. Metabotropic glutamate receptor subtype mGluR1alpha stimulates the secretion of the amyloid beta protein precursor ectodomain. J Neurochem. 69, 704-712 (1997). Abstract
16. De Strooper B, Annaert W. Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 2000 Jun;113 ( Pt 11):1857-70. Abstract
White F, Nicoll JA, Horsburgh K.
Alterations in ApoE and ApoJ in relation to degeneration and regeneration in a mouse model of entorhinal cortex lesion.
Exp Neurol. 2001 Jun;169(2):307-18.
Koudinov AR, Berezov TT, Koudinova NV.
The levels of soluble amyloid beta in different high density lipoprotein subfractions distinguish Alzheimer's and normal aging cerebrospinal fluid: implication for brain cholesterol pathology?.
Neurosci Lett. 2001 Nov 16;314(3):115-8.
Koudinova NV, Koudinov AR, Yavin E.
Alzheimer's Abeta1-40 peptide modulates lipid synthesis in neuronal cultures and intact rat fetal brain under normoxic and oxidative stress conditions.
Neurochem Res. 2000 May;25(5):653-60.
Koudinov AR, Koudinova NV.
Essential role for cholesterol in synaptic plasticity and neuronal degeneration.
FASEB J. 2001 Aug;15(10):1858-60.
Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles.
Neuron. 1999 Nov;24(3):521-9.
Huber G, Bailly Y, Martin JR, Mariani J, Brugg B.
Synaptic beta-amyloid precursor proteins increase with learning capacity in rats.
Neuroscience. 1997 Sep;80(2):313-20.
Heese K, Nagai Y, Sawada T.
Identification of a new synaptic vesicle protein 2B mRNA transcript which is up-regulated in neurons by amyloid beta peptide fragment (1-42).
Biochem Biophys Res Commun. 2001 Dec 21;289(5):924-8.
Wang C, Wurtman RJ, Lee RK.
Amyloid precursor protein and membrane phospholipids in primary cortical neurons increase with development, or after exposure to nerve growth factor or Abeta(1-40).
Brain Res. 2000 May 26;865(2):157-67.
von der Kammer H, Mayhaus M, Albrecht C, Andresen B, Klaudiny J, Demiralay C, Nitsch RM.
Regulation of gene expression by muscarinic acetylcholine receptors. A comprehensive approach for the identification of regulated genes.
Ann N Y Acad Sci. 2000;920:305-8.
Isacson O, Lin L.
Cholinergic modulation of amyloid processing and dementia in animal models of Alzheimer's disease.
Ann N Y Acad Sci. 2000;920:309-14.
Nitsch RM, Deng M, Growdon JH, Wurtman RJ.
Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion.
J Biol Chem. 1996 Feb 23;271(8):4188-94.
Nitsch RM, Deng A, Wurtman RJ, Growdon JH.
Metabotropic glutamate receptor subtype mGluR1alpha stimulates the secretion of the amyloid beta-protein precursor ectodomain.
J Neurochem. 1997 Aug;69(2):704-12.
De Strooper B, Annaert W.
Proteolytic processing and cell biological functions of the amyloid precursor protein.
J Cell Sci. 2000 Jun;113 ( Pt 11):1857-70.
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