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Selectively reduced expression of synaptic plasticity-related genes in amyloid precursor protein plus presenilin-1 transgenic mice

Academic Article
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Overview

authors

  • Dickey, C. A.
  • Loring, Jeanne
  • Montgomery, J.
  • Gordon, M. N.
  • Eastman, P. S.
  • Morgan, D.

publication date

  • June 2003

journal

  • Journal of Neuroscience  Journal

abstract

  • A critical question in Alzheimer's disease (AD) research is the cause of memory loss that leads to dementia. The amyloid precursor protein + presenilin-1 (APP+PS1) transgenic mouse is a model for amyloid deposition, and like AD, the mice develop memory deficits as amyloid deposits accumulate. We profiled gene expression in these transgenic mice by microarray and quantitative RT-PCR (qRT-PCR). At the age when these animals developed cognitive dysfunction, they had reduced mRNA expression of several genes essential for long-term potentiation and memory formation (Arc, Zif268, NR2B, GluR1, Homer-1a, Nur77/TR3). These changes appeared to be related to amyloid deposition, because mRNA expression was unchanged in the regions that did not accumulate amyloid. Transgene expression was similar in both amyloid-containing and amyloid-free regions of the brain. Interestingly, these changes occurred without apparent changes in synaptic structure, because a number of presynaptic marker mRNAs (growth-associated protein-43, synapsin, synaptophysin, synaptopodin, synaptotagmin, syntaxin) remained stable. Additionally, a number of genes related to inflammation were elevated in transgenic mice, primarily in the regions containing amyloid. In AD cortical tissue, the same memory-associated genes were downregulated. However, all synaptic and neuronal transcripts were reduced, implying that the loss of neurons and synapses contributed to these changes. We conclude that reduced expression of selected genes associated with memory consolidation are linked to memory loss in both circumstances. This suggests that the memory loss in APP+PS1 transgenic mice may model the early memory dysfunction in AD before the degeneration of synapses and neurons.

subject areas

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Amyloid
  • Amyloid beta-Protein Precursor
  • Animals
  • Brain
  • Disease Models, Animal
  • Disease Progression
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Inflammation
  • Long-Term Potentiation
  • Male
  • Membrane Proteins
  • Memory
  • Mice
  • Mice, Transgenic
  • Neuronal Plasticity
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction
  • Presenilin-1
  • RNA, Messenger
  • Synapses
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Research

keywords

  • Alzheimer's
  • IEGs
  • amyloid
  • cDNA microarray
  • immediate early genes
  • memory
  • real time PCR
  • transgenic
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Identity

International Standard Serial Number (ISSN)

  • 0270-6474

PubMed ID

  • 12832546
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Additional Document Info

start page

  • 5219

end page

  • 5226

volume

  • 23

issue

  • 12

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