Hippocampal spatial memory impairments caused by the familial Alzheimer's disease-linked presenilin 1 M146V mutation

Xiaoyan Sun, Vassilios Beglopoulos, Mark P. Mattson, Jie Shen

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


Mutations in presenilins (PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional inactivation of PS1 in the mouse postnatal forebrain leads to mild deficits in spatial learning and memory, whereas inactivation of both PS1 and PS2 results in severe memory and synaptic plasticity impairments, followed by progressive and substantial neurodegeneration. Here we investigate the effect of a familial Alzheimer's disease-linked PS1 missense mutation using knock-in (KI) mice, in which the wild-type PS1 allele is replaced with the M146V mutant allele. In the Morris water maze task, PS1 KI mice at 3 months of age exhibit reduced quadrant occupancy and platform crossing in the probe trial after 6 days of training, though their performance was normal in the probe trial after 12 days of training. By the age of 9 months, even after 12 days of training, PS1 homozygous KI mice still exhibit reduced platform crossing in the post-training probe trial. ELISA analysis revealed a selective increase in cortical levels of β-amyloid 42 in PS1 KI mice, whereas production of β-amyloid 40 was normal. Histological and quantitative real-time RT-PCR analyses showed normal gross hippocampal morphology and unaltered expression of three genes involved in inflammatory responses in PS1 KI mice. These results show hippocampal spatial memory impairments caused by the PS1 M146V mutation and age-related deterioration of the memory impairment, suggesting that PS1 KI mice are a valuable model system for the study of memory loss in AD.

Original languageEnglish (US)
Pages (from-to)6-15
Number of pages10
JournalNeurodegenerative Diseases
Issue number1
StatePublished - Aug 2005
Externally publishedYes


  • γ-secretase
  • Brain
  • Hippocampus
  • Knock-in mouse model
  • Presenilin
  • Spatial memory
  • Water maze task

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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