Characterization of stable complexes involving apolipoprotein E and the amyloid β peptide in Alzheimer's disease brain

Näslund, Jan; Thyberg, Johan; Tjernberg, Lars O.; Wernstedt, Christer; Karlström, Anders R.; Bogdanović, Nenad; Gandy, Samuel E.; Lannfelt, Lars; Terenius, Lars; Nordstedt, Christer

doi:10.1016/0896-6273(95)90079-9

Cited by 192 publications

(136 citation statements)

References 34 publications

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“…This is bolstered by data obtained from purification and characterization of apoE:Aβ complexes from the brains of subjects with various APOE genotypes, in which we demonstrated no effect of APOE genotype on the quality or composition of the apoE:Aβ complex (39).…”

Section: How Does Apoe ε4 Increase the Risk For Ad?supporting

confidence: 52%

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Gandy¹

2005

Journal of Clinical Investigation

139

151

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For approximately 80 years following Alzheimer's description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid β (Aβ) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Aβ peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Aβ accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Aβ in common AD.

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Section: How Does Apoe ε4 Increase the Risk For Ad?supporting

confidence: 52%

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Gandy¹

2005

Journal of Clinical Investigation

139

151

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“…It has been documented that apoE co-localizes with amyloid deposits in AD patients and can also bind soluble A␤ found in the brain, cerebrospinal fluid, and plasma (67)(68)(69)(70)(71). ApoE directly interacts with A␤, and this binding is both isoform-and lipidation status-dependent (36,37,69,(72)(73)(74).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels

Lee

Tse

Smith

et al. 2012

Journal of Biological Chemistry

143

125

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Background: Intracellular A␤ degradation is enhanced in the presence of apoE. Results: Lowering cellular cholesterol levels facilitates intracellular trafficking of A␤ to lysosomes and enhances its degradation. Conversely, increasing cholesterol levels retards the delivery and inhibits degradation of A␤. Conclusion:The cholesterol efflux function of apoE mediates its ability to promote A␤ degradation. Significance: We demonstrate a direct role for cholesterol in AD.

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“…ApoE isotype inheritance modulates the prevalence, age of onset, and the burden of pathology in sporadic AD (4,5). ApoE binds A␤ with high affinity and acts as a ''double-edged sword'' in the pathomechanism of AD, being involved in both clearance of A␤ across the BBB (6,7) and the promotion of its deposition (5,8,9). All human apoE isoforms (E2, E3, and E4) promote in vivo assembly of A␤ synthetic peptide into fibrils and enhance A␤ toxicity in tissue culture with E4 producing the most striking effect (10)(11)(12).…”

mentioning

confidence: 99%

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

Sadowski¹,

Pankiewicz²,

Scholtzova³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

149

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The amyloid-␤ (A␤) cascade hypothesis of Alzheimer's disease (AD) maintains that accumulation of A␤ peptide constitutes a critical event in the early disease pathogenesis. The direct binding between A␤ and apolipoprotein E (apoE) is an important factor implicated in both A␤ clearance and its deposition in the brain's parenchyma and the walls of meningoencephalic vessels as cerebral amyloid angiopathy. With the aim of testing the effect of blocking the apoE/A␤ interaction in vivo as a potential novel therapeutic target for AD pharmacotherapy, we have developed A␤12-28P, which is a blood-brain-barrier-permeable nontoxic, and nonfibrillogenic synthetic peptide homologous to the apoE binding site on the full-length A␤. A␤12-28P binds with high affinity to apoE, preventing its binding to A␤, but has no direct effect on A␤ aggregation. A␤12-28P shows a strong pharmacological effect in vivo. Its systemic administration resulted in a significant reduction of A␤ plaques and cerebral amyloid angiopathy burden and a reduction of the total brain level of A␤ in two AD transgenic mice models. The treatment did not affect the levels of soluble A␤ fraction or A␤ oligomers, indicating that inhibition of the apoE/A␤ interaction in vivo has a net effect of increasing A␤ clearance over deposition and at the same time does not create conditions favoring formation of toxic oligomers. Furthermore, behavioral studies demonstrated that treatment with A␤12-28P prevents a memory deficit in transgenic animals. These findings provide evidence of another therapeutic approach for AD.Alzheimer's pathology ͉ memory loss prevention ͉ peptide ͉ transgenic mice ͉ treatment A lzheimer's disease (AD) is the most common neurodegenerative disease worldwide, characterized by a progressive dysfunction in multiple cognitive domains and complex neuropathological features that include accumulation of amyloid-␤ (A␤) followed by synaptic dysfunction, formation of neurofibrillary tangles, and neuronal loss. With the expected increase in AD prevalence, as a function of the population aging, effective treatment for AD is critically needed. Multiple lines of evidence indicate that a disturbance of A␤ homeostasis is a paramount event in early disease pathogenesis (1). A␤ is a hydrophobic 39-to 43-aa peptide, which is derived from cleavage of a larger, synaptic transmembrane protein, the amyloid precursor protein (APP) (2). The accumulation of A␤ in the brain is determined by the rate of its generation versus in situ proteolytic degradation and clearance across the blood-brain-barrier [BBB; for review see Tanzi et al. (3)]. In the setting of increased concentration, A␤ monomers assemble into oligomers and fibrils and eventually become deposited, forming parenchymal plaques and cerebral amyloid angiopathy (CAA).Inheritance of the apolipoprotein E4 (apoE4) allele is the strongest genetic risk factor identified so far. ApoE isotype inheritance modulates the prevalence, age of onset, and the burden of pathology in sporadic AD (4, 5). ApoE binds A␤ with high affinity a...

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Characterization of stable complexes involving apolipoprotein E and the amyloid β peptide in Alzheimer's disease brain

Cited by 192 publications

References 34 publications

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels

Blocking the apolipoprotein E/amyloid-β interaction as a potential therapeutic approach for Alzheimer's disease

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