Chronic cerebral hypoperfusion accelerates amyloid β deposition in APP SwInd transgenic mice

Abstract

Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid β 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 (APP SwInd) 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 β 1–40 (Aβ 1–40), amyloid β 1–42 (Aβ 1–42), as well as Western blotting and filter assay for Aβ. Another batch of the littermates of APP SwInd 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 β 1–40 immunoreactivity was found in a few axons in the white matter after BCAS, whereas Aβ 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 Aβ 1–40 and Aβ 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 Aβ fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased Aβ fibrils and induced Aβ deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease.