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 journalArticle

44 Citations (Scopus)

Abstract

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
Volume6
Issue number1
DOIs
Publication statusPublished - 07-02-2011

Fingerprint

Amyloid beta-Protein Precursor
amyloid
Application programs
Amyloid
Metabolism
cognition
Cognition
Carotid Stenosis
metabolism
carotid arteries
mice
Bearings (structural)
Blood Vessels
blood vessels
Aptitude
Analysis of variance (ANOVA)
Silver
Design of experiments
Neurons
Brain

All Science Journal Classification (ASJC) codes

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

Cite this

Yamada, M., Ihara, M., Okamoto, Y., Maki, T., Washida, K., Kitamura, A., ... Takahashi, R. (2011). The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in app overexpressing mice. PloS one, 6(1), [e16567]. https://doi.org/10.1371/journal.pone.0016567
Yamada, Mahito ; Ihara, Masafumi ; Okamoto, Yoko ; Maki, Takakuni ; Washida, Kazuo ; Kitamura, Akihiro ; Hase, Yoshiki ; Ito, Hidefumi ; Takao, Keizo ; Miyakawa, Tsuyoshi ; Kalaria, Raj N. ; Tomimoto, Hidekazu ; Takahashi, Ryosuke. / The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in app overexpressing mice. In: PloS one. 2011 ; Vol. 6, No. 1.
@article{63de585728f14257af2bd94a1e61ab25,
title = "The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in app overexpressing mice",
abstract = "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.",
author = "Mahito Yamada and Masafumi Ihara and Yoko Okamoto and Takakuni Maki and Kazuo Washida and Akihiro Kitamura and Yoshiki Hase and Hidefumi Ito and Keizo Takao and Tsuyoshi Miyakawa and Kalaria, {Raj N.} and Hidekazu Tomimoto and Ryosuke Takahashi",
year = "2011",
month = "2",
day = "7",
doi = "10.1371/journal.pone.0016567",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "1",

}

Yamada, M, Ihara, M, Okamoto, Y, Maki, T, Washida, K, Kitamura, A, Hase, Y, Ito, H, Takao, K, Miyakawa, T, Kalaria, RN, Tomimoto, H & Takahashi, R 2011, 'The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in app overexpressing mice', PloS one, vol. 6, no. 1, e16567. https://doi.org/10.1371/journal.pone.0016567

The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in app overexpressing mice. / Yamada, Mahito; Ihara, Masafumi; Okamoto, Yoko; Maki, Takakuni; Washida, Kazuo; Kitamura, Akihiro; Hase, Yoshiki; Ito, Hidefumi; Takao, Keizo; Miyakawa, Tsuyoshi; Kalaria, Raj N.; Tomimoto, Hidekazu; Takahashi, Ryosuke.

In: PloS one, Vol. 6, No. 1, e16567, 07.02.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The influence of chronic cerebral hypoperfusion on cognitive function and amyloid β metabolism in app overexpressing mice

AU - Yamada, Mahito

AU - Ihara, Masafumi

AU - Okamoto, Yoko

AU - Maki, Takakuni

AU - Washida, Kazuo

AU - Kitamura, Akihiro

AU - Hase, Yoshiki

AU - Ito, Hidefumi

AU - Takao, Keizo

AU - Miyakawa, Tsuyoshi

AU - Kalaria, Raj N.

AU - Tomimoto, Hidekazu

AU - Takahashi, Ryosuke

PY - 2011/2/7

Y1 - 2011/2/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79551551961&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79551551961&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0016567

DO - 10.1371/journal.pone.0016567

M3 - Article

C2 - 21305033

AN - SCOPUS:79551551961

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 1

M1 - e16567

ER -