|It is recently accepted that vascular risk factors linked to cerebrovascular disease and stroke significantly increase the risk of developing AD. Since ischemic events in the elderly induce amyloid precursor protein, amyloid Î² and tau pathology, cerebral ischemia might be a key factor in the formation of the full picture of Alzheimer neurodegeneration over years. Most AD cases show silent ischemic episodes that can cause neuronal death, blood-brain barrier changes, inflammation response, neurofibrillary tangles and amyloid plaque formation. Alzheimer neuronal death occurs by defective cholesterol trafficking within the endocytic/lysosomal pathway caused by activated calpain-mediated cleavage of oxidative stress-injured Hsp70.1. Hsp70.1 dysfunction due to its cleavage leads to deprivation of ceramide at the lysosomal membrane via decrease of BMP, and eventually to destabilization of lysosomal membranes.
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