Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis

R. Wang, Kelly Dineley, J. D. Sweatt, H. Zheng

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Alzheimer's disease is a learning and memory disorder pathologically characterized by the deposition of β-amyloid plaques and loss of neurons and synapses in affected areas of the brain. Mutations in presenilin 1 (PS1) lead to the most aggressive form of familial Alzheimer's disease (FAD), and are associated with accelerated plaque deposition. However, since the function of PS1 is pleiotropic, we reasoned that the FAD mutations may alter multiple PS1-mediated pathways, and the combination of which may account for the early onset nature of the disease phenotype. Using the PS1M146V knockin mice in which the M146V mutation was incorporated into the endogenous mouse PS1 gene, we report here that the FAD mutation results in impaired hippocampus-dependent associative learning, as measured by a contextual fear conditioning paradigm, at 3 months of age. This is correlated with reduced adult neurogenesis in the dentate gyrus. However, short-term and long-term synaptic plasticity in both area CA1 and dentate gyrus are not affected. Our results suggest that impaired adult neurogenesis may contribute to the memory deficit associated with FAD.

Original languageEnglish (US)
Pages (from-to)305-312
Number of pages8
JournalNeuroscience
Volume126
Issue number2
DOIs
StatePublished - 2004
Externally publishedYes

Fingerprint

Presenilin-1
Neurogenesis
Alzheimer Disease
Learning
Mutation
Dentate Gyrus
Memory Disorders
Neuronal Plasticity
Learning Disorders
Amyloid Plaques
Synapses
Fear
Hippocampus
Phenotype
Neurons
Brain
Genes

Keywords

  • 5-bromodeoxyuridine
  • ACSF
  • AD
  • Alzheimer's disease
  • amyloid precursor protein
  • APP
  • artificial cerebrospinal fluid
  • BrdU
  • conditioned stimulus
  • CS
  • dentate gyrus
  • DG
  • FAD
  • fear conditioning
  • hippocampus
  • knockin mice
  • neurogenesis
  • presenilin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. / Wang, R.; Dineley, Kelly; Sweatt, J. D.; Zheng, H.

In: Neuroscience, Vol. 126, No. 2, 2004, p. 305-312.

Research output: Contribution to journalArticle

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