Accumulation of the protein amyloid-? is a hallmark of the condition called cerebral amyloid angiopathy, and is observed in approximately 80% of patients with Alzheimer?s disease, a most prevalent cause of dementia. Although dementia is a consequence of loss of neurons, studies show that impairment in the control of blood flow to active regions of the brain occurs before neuronal death is evident. Neurons have a limited capacity to store energy and nutrients necessary for their optimal function, thus relying on the cerebral circulation for delivery of necessary nutrients. One hallmark of the brain circulation is its ability to remarkably control blood perfusion to regions of increased neuronal activity, a process known as functional hyperemia. This localized increase in blood perfusion to match neuronal activity is a consequence of neurovascular coupling (NVC), in which neurons, glial cells (mainly astrocytes) and endothelial cells (EC) act in concert to promote vasodilation of upstream arterioles, shunting blood to active neurons. Functional hyperemia and NVC are known to occur for more than a century, but most of its mediators and cellular effectors remain unknown. Active neurons release a plethora of transmitters that activates astrocytes, a type of non-neuronal cells in the brain. Astrocytes, on the other hand, emit projections that envelop cerebral capillaries, called astrocytic end-feet. Therefore, substances released from activated astrocytes can then act on cerebral capillary EC to signal to the vasculature the metabolic status of a particular neuronal population. Capillary EC do not possess contractile activity, thus control of blood perfusion through a capillary bed will fall on the contractile member of the cerebral microvascular tree: the upstream parenchymal arteriole. For capillary EC to cause dilation of upstream arterioles, it is necessary that a sensor in capillary EC initiates a signal that is rapidly transmitted to upstream arterioles. This project focuses on the effects of one of such signals, the N-Methyl-D-Aspartate receptor (NMDAR) and its role in generating a propagated vasodilatory response from the capillaries to arterioles in the brain. Further, studies proposed here will also investigate how amyloid-? can interfere in this essential process in the brain, as amyloid-? was shown to reduce NMDAR activity in neurons. Thus, it is possible that one of the mechanisms by which amyloid-? impairs NVC in patients with cerebral amyloid angiopathy is by reducing the activity of NMDAR in cerebral capillary EC.
Cerebral amyloid angiopathy, caused by accumulation of the peptide amyloid-? in the brain, is observed in 80% of patients with Alzheimer?s disease. One possible cause of the dementia associated by amyloid-? accumulation is impairment in localized control of cerebral blood flow, an essential process for maintenance of optimal function in neurons. This research project focus on investigating mechanisms regulating this dynamic control of cerebral blood flow by capillaries, and how amyloid-? negatively impact this process. The findings of this study may yield new possible therapies to improve the quality of life of patients suffering from cerebral amyloid angiopathy.
