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. 2011 Jan 27;6(1):e16567.
doi: 10.1371/journal.pone.0016567.

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

Affiliations

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

Mahito Yamada et al. PLoS One. .

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 (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 ×ばつ 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Interaction between APP overexpression and chronic cerebral hypoperfusion.
Barnes maze test showed that APPSw/Ind-Tg/BCAS mice exhibited prolonged latency to reach the desired target (A), increased number of errors (B), and increased distance before reaching the desired target (C) compared to the other groups.
Figure 2
Figure 2. Neuronal density in the cerebral cortex and the hippocampal CA1 and CA3 areas.
(A) The schematic illustration of the regions of interest depicted in the cerebral cortex (size, ×ばつ0.5 mm) and the hippocampal CA1 and CA3 areas (×ばつ0.25 mm each) of the coronal section of the brain. (B) The density of Nissl-stained neurons was lowest in APPSw/Ind-Tg/BCAS mice.
Figure 3
Figure 3. Chronic cerebral hypoperfusion affected the number of silver-stained cored plaques in the APPSw/Ind-Tg mice.
Modified Bielschowsky staining showed cored plaques in the hippocampus (A, B, G, H) and the cerebral cortex (C, D), and diffuse plaques in the hippocampus (E, F) of the APPSw/Ind-Tg/sham mice (n = 6; A, C, E, G) and APPSw/Ind-Tg/BCAS mice (n = 4; B, D, F, H). Number of cored plaques was counted in the cortex and the hippocampus (I). Scale bars: 400 μm (A, B), 300 μm (C-F), 80 μm (G, H).
Figure 4
Figure 4. Chronic cerebral hypoperfusion reduced the Aβ1-42 stained area in the APPSw/Ind-Tg mice.
Immunohistochemistry for Aβ1-42 showed intense staining in the hippocampus (A, B, E, F) and in the cerebral cortex (C, D) of the APPSw/Ind-Tg/sham mice (n = 4; A, C, E, G) and APPSw/Ind-Tg/BCAS mice (n = 6; B, D, F, H). (I) The area positive for Aβ1-42 was analysed in the cortex and the hippocampus. Scale bars: 400 μm (A, B), 300 μm (C–F), 80 μm (G, H).
Figure 5
Figure 5. Chronic cerebral hypoperfusion increased filter-trap Aβ in the extracellular-enriched, soluble brain fraction.
(A) Filter-trap, Aβ-immunoreactive spot density was increased in samples from BCAS-treated mice, compared to sham-operated littermates. (B) Spot density was significantly increased in BCAS-treated mice (paired t-test; p = 0.0231, n = 4).

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