Presenilins and APP in neuritic and synaptic plasticity: Implications for the pathogenesis of Alzheimer's disease

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)167-196
Number of pages30
JournalNeuroMolecular Medicine
Volume2
Issue number2
DOIs
StatePublished - 2002

Fingerprint

Presenilins
Neuronal Plasticity
Amyloid beta-Protein Precursor
Alzheimer Disease
Mutation
Synapses
Learning
Calcium
Amino Acid Transport System X-AG
Synaptic Membranes
Membrane Transport Proteins
Facilitative Glucose Transport Proteins
Amyloid
Endoplasmic Reticulum
Transgenic Mice
Oxidative Stress
Homeostasis
Ions

Keywords

  • Alzheimer's disease
  • Calcium
  • Glutamate receptors
  • Hippocampus
  • Learning and memory
  • LTP and LTD

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Cell Biology

Cite this

Presenilins and APP in neuritic and synaptic plasticity : Implications for the pathogenesis of Alzheimer's disease. / Chan, Sic L.; Furukawa, Katsutoshi; Mattson, Mark P.

In: NeuroMolecular Medicine, Vol. 2, No. 2, 2002, p. 167-196.

Research output: Contribution to journalArticle

Chan, Sic L. ; Furukawa, Katsutoshi ; Mattson, Mark P. / Presenilins and APP in neuritic and synaptic plasticity : Implications for the pathogenesis of Alzheimer's disease. In: NeuroMolecular Medicine. 2002 ; Vol. 2, No. 2. pp. 167-196.
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