Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice

Department of Neurology, Kyoto University, Sakyo-ku, Kyoto 606-8504, Japan.
Brain research (Impact Factor: 2.84). 08/2009; 1294:202-10. DOI: 10.1016/j.brainres.2009.07.078
Source: PubMed


Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid beta deposition in amyloid protein precursor transgenic (APP-Tg) mouse. At 5, 8, and 11 months of age, C57Bl/6J male mice overexpressing a mutant form of the human APP bearing the both Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd) and their litterrmates were subjected to either sham operation or bilateral carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm (short-period group). One month after the sham operation or BCAS, these animals were examined by immunohistochemistry for glial fibrillary acidic protein, amyloid beta(1-40) (Abeta(1-40)), amyloid beta(1-42) (Abeta(1-42)), as well as Western blotting and filter assay for Abeta. Another batch of the littermates of APPSwInd mice were subjected to either sham operation or BCAS at 3 months and were examined in the same manner after survival for 9 months (long-period group). In the BCAS-treated group, the white matter was rarefied and astroglia was proliferated. Amyloid beta(1-40) immunoreactivity was found in a few axons in the white matter after BCAS, whereas Abeta(1-42) was accumulated in the scattered cortical neurons and the axons at ages of 6 months and thereafter in the short- and long-period groups. In the neuropil, both Abeta(1-40) and Abeta(1-42) were deposited in the sham-operated and BCAS-treated mice at ages of 9 and 12 months. There were no differences between the short-period group at ages of 12 months and the long-period group. Filter assay showed an increase of Abeta fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased Abeta fibrils and induced Abeta deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease.

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    • "Rarefied white matter, proliferated astroglia, and Ab 1-40 immunoreactivity appear in some axons in the white matter of APP-Tg mice soon after BCAS, whereas Ab 1-42 accumulates later in the scattered cortical neurons and their axons (Kitaguchi et al. 2009). BCAS also exacerbates Ab aggregation, neuronal loss, and learning impairment in APP-Tg mice (Yamada et al. 2011). "
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    • "Hence cerebral hypoperfusion promoting Ab deposition, at least in part, may trigger/accelerate the AD type pathological changes. Finally, there is universality in the effect of cerebral hypoperfusion on amyloid cascade, in that overexpression of Ab and enhanced neuronal pathology/loss may exacerbate AD-type cognitive impairment in transgenic mice (C57Bl/6 J/ (APP(Sw/Ind)-Tg; APP bearing Swedish (K670 N/M671L) and the Indiana (V717F) mutations (APPSwInd)), rats, as well as humans (Kitaguchi et al. 2009; Yamada et al. 2011). "

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    • "Hypoperfusion and hypoxia caused by vascular insufficiency may also facilitate Ab production by activating the APP cleav - age enzyme b - secretase ( Kitaguchi et al . , 2009 ; Sun et al . , 2006 ; Tesco et al . , 2007 ; Wen et al . , 2004a ) . Cerebral ischemia promotes amyloid plaque formation ( Garcia - Alloza et al . , 2011 ; Kitaguchi et al . , 2009 ; Okamoto et al . , 2012 ) , and tau phos - phorylation ( Koike et al . , 2010 ; Wen et al . , 2007 ; 2004b ) . The vascular effects of Ab may also impair the clearance of the pep - tide , a key factor in brain Ab accumulation in sporadic AD ( Mawuenyega et al . , 2010 ) . The vascular pathway is estimated to be a major route of removal"
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