Cerebral Vascular Dysfunction in Alzheimer's Disease.

摘要

The neurovascular unit is comprised of brain endothelium, pericytes, vascular smooth muscle cells (VSMC), astrocytes, microglia and neurons. Complex and dynamic communication between the cells of the neurovascular unit is essential for maintaining normal brain function. Recently, the role of cerebral vascular dysfunction has been highlighted in several neurodegenerative disease processes, such as Alzheimer's disease (AD). Here, I utilized multiple experimental models to test the central hypothesis that cerebral vascular dysfunction can contribute to AD pathogenesis. We found that (1) cerebral vascular dysfunction, mediated by pericyte deficiency in adult mice, can lead to neurodegeneration, (2) molecular changes specifically within brain VSMC can contribute to the development of AD-like pathologies in the cerebral cortex and (3) a known inherited genetic risk factor for AD may contribute to the cerebral vascular damage that is present during disease pathogenesis.;First, pericytes play a key role in the development of the cerebral microcirculation, although the exact role of pericytes in the adult brain remains elusive. Using adult viable mice with varying degrees of pericyte deficiency, we show that pericyte loss leads to reduction in brain microcirculation causing chronic perfusion stress and hypoxia, and blood-brain barrier breakdown associated with brain accumulation of vasculotoxic and/or neurotoxic serum proteins. Age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, and learning and memory impairment. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in progressive age-dependent vascular-mediated neurodegeneration. This study provides proof-of-principle evidence supporting the hypothesis that vascular damage may initiate neurodegenerative disease processes.;Next, we investigate the molecular basis of a vascular-specific insult mediated by amyloid beta-peptide (Abeta) deposition in cerebral vessels, called cerebral amyloid angiopathy, which contributes to AD pathogenesis. Here, we report increased levels of two proteins, serum response factor (SRF) and myocardin (MYOCD), in cerebral VSMC in AD and in two mouse models of AD generates an Abeta non-clearing VSMC phenotype via transactivation of sterol regulatory element binding protein-2, which downregulates low density lipoprotein receptor-related protein-I, a key A13 clearance receptor. Hypoxia stimulated SRF/MYOCD expression in human cerebral VSMC and in an AD mouse model. We suggest SRF and MYOCD constitute a new transcriptional switch controlling Abeta cerebrovascular clearance and progression of AD. This study supports the hypothesis that molecular changes specifically in vascular cells of the neurovascular unit may contribute to AD pathogenesis.;Finally, the apolipoprotein E4 (APOE4) allele is an inherited genetic risk factor for the development of neurological disorders that are associated with neurovascular dysfunction, including AD. The mechanism by which APOE affects the neurovascular unit is largely unknown. Here, we report that APOE2 and APOE3, but not APOE4, effectively maintain blood-brain barrier (BBB) integrity, brain vascular density and cerebral blood flow (CBF) in Apoe-/- mice. We next found an increase in peptidylprolyl isomerase A (PPIA), a proinflammatory cytokine that mediates extracellular matrix degradation and endothelial and neuronal apoptosis also known as cyclophilin A. expression in the brains of Apoe -/- and APOE4-expressing mice. Interestingly, lack of PPIA or PPIA inhibition with cyclosporine inhibited BBB disruption and CBF reductions and improved neuronal spine density in Apoe-/- and APOE4-expressing mice. Our findings suggest APOE plays a role in maintaining neurovascular integrity, and PPIA may be a therapeutic target for neurovascular dysfunction present in AD.;In summary, cerebral vascular dysfunction, whether initiated by a loss of key brain vascular cells, neurovascular cell-specific molecular changes and/or genetic predisposition, may be an important target for the development of therapeutics for AD and other neurodegenerative disease processes with associated cerebral vascular dysfunction.