Chronic cerebral hypoperfusion accelerates amyloid β deposition in APPSwInd transgenic mice
ABSTRACT 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.
Full-textDOI: · Available from: Takeshi Kihara, Sep 02, 2015
- SourceAvailable from: Cheng-Xin Gong
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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). "
ABSTRACT: Chronic cerebral hypoperfusion (CCH) is a common consequence of various cerebral vascular disorders and hemodynamic and blood changes. Recent studies have revealed an important role of CCH in neurodegeneration and dementia, including vascular dementia and Alzheimer's disease (AD). This article reviews the recent advances in understanding CCH-induced neurodegeneration and AD-related brain pathology and cognitive impairment. We discuss the causes and assessment of CCH, the possible mechanisms by which CCH promotes Alzheimer-like pathology and neurodegeneration, and animal models of CCH. It appears that CCH promotes neurodegeneration and AD through multiple mechanisms, including induction of oxidative stress, Aβ accumulation and aggravation, tau hyperphosphorylation, synaptic dysfunction, neuronal loss, white matter lesion, and neuroinflammation. Better understanding of the mechanisms of CCH will help develop therapeutic strategies for preventing and treating neurodegeneration, including sporadic AD and vascular dementia, caused by CCH.Cellular and Molecular Neurobiology 10/2014; 35(1). DOI:10.1007/s10571-014-0127-9 · 2.20 Impact Factor
- "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"
ABSTRACT: Vascular cognitive impairment defines alterations in cognition, ranging from subtle deficits to full-blown dementia, attributable to cerebrovascular causes. Often coexisting with Alzheimer's disease, mixed vascular and neurodegenerative dementia has emerged as the leading cause of age-related cognitive impairment. Central to the disease mechanism is the crucial role that cerebral blood vessels play in brain health, not only for the delivery of oxygen and nutrients, but also for the trophic signaling that inextricably links the well-being of neurons and glia to that of cerebrovascular cells. This review will examine how vascular damage disrupts these vital homeostatic interactions, focusing on the hemispheric white matter, a region at heightened risk for vascular damage, and on the interplay between vascular factors and Alzheimer's disease. Finally, preventative and therapeutic prospects will be examined, highlighting the importance of midlife vascular risk factor control in the prevention of late-life dementia.Neuron 11/2013; 80(4):844-866. DOI:10.1016/j.neuron.2013.10.008 · 15.98 Impact Factor