Can disturbed brain microcirculation cause Alzheimer’s disease?

Abstract

Recent ultrastructural studies demonstrate characteristic and extensive angio-architectural distortions of cerebral capillaries in Alzheimer's brains. Alzheimer's disease subjects additionally show reduced cerebral blood flow (CBF), glucose metabolism and oxygen utilization which appear inversely proportional to the disease severity. These findings led us to develop a hypothetical model which appears consistent with the pathogenesis and progression of AD. During ageing, brain capillaries (site of the blood-brain barrier) may undergo progressive degeneration caused by amyloid deposits, thickened basement membrane, cerebral atrophy, reduced vessel elasticity, or genetic predisposition. When these structural abnormalities of the brain microvasculature begin to interfere with basic laws of fluid dynamics, haemorheological compromise will result in cerebral capillary resistance, high blood viscosity, abnormal flow patterns, and changes in shear stress and shear rate in vessel walls. The net effect is chronic 'disturbed' blood flow to the brain that impairs the delivery of essential nutrients, particularly oxygen and glucose, to cerebral neurons. As ischaemic-sensitive neurons lower their oxidative phosphorylation and ATP production to subfunctional levels, they release a diffusible glial mitogen that directly stimulates reactive astrocytosis. These reactive glia differ significantly from normal glia because they proliferate mostly in response to brain injury and can spread to unaffected tissue. It has been suggested that amyloid precursor protein (APP) may be expressed from reactive glia following neuronal injury thus providing the nidus of plaque formation. As brain tissue space is invaded by reactive glia and microglia, neuronal cytoskeletal damage can result in neurofibrillary tangles.(ABSTRACT TRUNCATED AT 250 WORDS)