Impacts of membrane biophysics in Alzheimer's disease: From amyloid precursor protein processing to Aβ peptide-induced membrane changes

James C M Lee, Sholpan Askarova, Xiaoguang Yang

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14 Citations (Scopus)

Abstract

An increasing amount of evidence supports the notion that cytotoxic effects of amyloid-β peptide (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD), are strongly associated with its ability to interact with membranes of neurons and other cerebral cells. Aβ is derived from amyloidogenic cleavage of amyloid precursor protein (AβPP) by β- and γ-secretase. In the nonamyloidogenic pathway, AβPP is cleaved by α-secretases. These two pathways compete with each other, and enhancing the non-amyloidogenic pathway has been suggested as a potential pharmacological approach for the treatment of AD. Since AβPP, α-, β-, and γ-secretases are membrane-associated proteins, AβPP processing and Aβ production can be affected by the membrane composition and properties. There is evidence that membrane composition and properties, in turn, play a critical role in Aβ cytotoxicity associated with its conformational changes and aggregation into oligomers and fibrils. Understanding the mechanisms leading to changes in a membrane's biophysical properties and how they affect AβPP processing and Aβ toxicity should prove to provide new therapeutic strategies for prevention and treatment of AD.

Original languageEnglish
Article number134971
JournalInternational Journal of Alzheimer's Disease
DOIs
Publication statusPublished - 2011
Externally publishedYes

Fingerprint

Biophysics
Amyloid beta-Protein Precursor
Amyloid Precursor Protein Secretases
Alzheimer Disease
Peptides
Membranes
Amyloidogenic Proteins
Serum Amyloid A Protein
Aptitude
Protein Precursors
Amyloid Plaques
Amyloid
Membrane Proteins
Pharmacology
Neurons

ASJC Scopus subject areas

  • Clinical Neurology
  • Behavioral Neuroscience
  • Cognitive Neuroscience
  • Ageing
  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

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abstract = "An increasing amount of evidence supports the notion that cytotoxic effects of amyloid-β peptide (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD), are strongly associated with its ability to interact with membranes of neurons and other cerebral cells. Aβ is derived from amyloidogenic cleavage of amyloid precursor protein (AβPP) by β- and γ-secretase. In the nonamyloidogenic pathway, AβPP is cleaved by α-secretases. These two pathways compete with each other, and enhancing the non-amyloidogenic pathway has been suggested as a potential pharmacological approach for the treatment of AD. Since AβPP, α-, β-, and γ-secretases are membrane-associated proteins, AβPP processing and Aβ production can be affected by the membrane composition and properties. There is evidence that membrane composition and properties, in turn, play a critical role in Aβ cytotoxicity associated with its conformational changes and aggregation into oligomers and fibrils. Understanding the mechanisms leading to changes in a membrane's biophysical properties and how they affect AβPP processing and Aβ toxicity should prove to provide new therapeutic strategies for prevention and treatment of AD.",
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