The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in app overexpressing mice

Mahito Yamada, Masafumi Ihara, Yoko Okamoto, Takakuni Maki, Kazuo Washida, Akihiro Kitamura, Yoshiki Hase, Hidefumi Ito, Keizo Takao, Tsuyoshi Miyakawa, Raj N. Kalaria, Hidekazu Tomimoto, Ryosuke Takahashi

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)


Background and Purpose: Cognitive impairment resulting from cerebrovascular insufficiency has been termed vascular cognitive impairment, and is generally accepted to be distinct from Alzheimer's disease resulting from a neurodegenerative process. However, it is clear that this simple dichotomy may need revision in light of the apparent occurrence of several shared features between Alzheimer's disease and vascular cognitive impairment. Nevertheless, it still remains largely unknown whether the burden of vascular- and Alzheimer-type neuropathology are independent or interdependent. Therefore, we investigated whether chronic cerebral hypoperfusion influences cognitive ability or amyloid β deposition in amyloid precursor protein (APP) overexpressing transgenic mice. Methods: Two months old mice overexpressing a mutant form of the human APP bearing both the Swedish and Indiana mutations (APPSw/Ind-Tg mice), or their wild-type littermates, were subjected to chronic cerebral hypoperfusion with bilateral common carotid artery stenosis (BCAS) using microcoils or sham operation. Barnes maze test performance and histopathological findings were analyzed at eight months old by 2×2 factorial experimental designs with four groups. Results: BCAS-operated APPSw/Ind-Tg mice showed significantly impaired learning ability compared to the other three groups of mice. Two-way repeated measures analysis of variance showed a synergistic interaction between the APP genotype and BCAS operation in inducing learning impairment. The cognitive performances were significantly correlated with the neuronal densities. BCAS significantly reduced the density of Nissl-stained neurons and silver-stained cored plaques in the hippocampus of APPSw/Ind-Tg mice but increased the amount of filter-trap amyloid β in the extracellular-enriched soluble brain fraction, compared to those from sham operated mice. Conclusions: The results suggest interaction between chronic cerebral hypoperfusion and APPSw/Ind overexpression in cognitive decline in mice through enhanced neuronal loss and altered amyloid β metabolism.

Original languageEnglish
Article numbere16567
JournalPloS one
Issue number1
Publication statusPublished - 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General


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