title: The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in APP overexpressing mice.
abstract: OBJECTIVE
  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 (APP(Sw/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 APP(Sw/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 APP(Sw/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 APP(Sw/Ind) overexpression in cognitive decline in mice through enhanced neuronal loss and altered amyloid β metabolism.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Mahito
authors.initials: M
authors.lastname: Yamada
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Washida
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kitamura
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Hase
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000008:administration & dosage / Q000235:genetics*; D000818:Animals; D016893:Carotid Stenosis; D002561:Cerebrovascular Disorders / Q000150:complications*; D002908:Chronic Disease; D003072:Cognition Disorders / Q000209:etiology*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor