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Presenilins and APP in neuritic and synaptic plasticity

Implications for the pathogenesis of Alzheimer’s disease

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Abstract

A key neuropathological hallmark of Alzheimer’s disease (AD) is the loss of neocortical and hippocampal synapses, which is closely correlated with the degree of memory impairment. Mutations in the genes encoding the amyloid precursor protein (APP) and presenilins are responsible from some cases of early-onset autosomal-dominant AD. This article reviews the current understanding of how alterations in the cellular functions of APP and presenilins may result in the dysfunction and degeneration of synapses in AD. APP mutations result in increased production/aggregation of amyloid β-peptide (Aβ), which induces oxidative stress, resulting in the impairment of synaptic membrane ion, glutamate, and glucose transporters. APP mutations may also compromise the production and/or function of secreted forms of APP that are believed to play important roles in learning and memory processes. Presenilin (PS1) mutations result in a major defect in endoplasmic reticulum (ER) calcium regulation, which may perturb synaptic function in ways that lead to impaired synaptic plasticity and neuronal degeneration. Studies in transgenic mice that express APP and PS1 mutations have provided evidence that the mutations result in altered cellular calcium homeostasis and synaptic plasticity, and impaired learning and memory. This article provides a brief review of the pathophysiological interactions of APP and presenilins with synaptic proteins, and discusses how AD-linked mutations in APP and PS1 may disrupt synaptic processes that contribute to memory formation.

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Authors and Affiliations

  1. Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 21224, Baltimore, MD

    Sic L. Chan, Katsutoshi Furukawa & Mark P. Mattson

  2. Department of Neuroscience, Johns Hopkins University, School of Medicine, 21205, Baltimore, MD

    Mark P. Mattson

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  1. Sic L. Chan
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Correspondence to Sic L. Chan.

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Chan, S.L., Furukawa, K. & Mattson, M.P. Presenilins and APP in neuritic and synaptic plasticity. Neuromol Med 2, 167–196 (2002). https://doi.org/10.1385/NMM:2:2:167

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