Neurovascular unit dysfunction: A vascular component of Alzheimer disease?

The structural and functional integrity of the CNS depends on the coupling between neural activity and cerebral blood flow (CBF) and the regulation of transport across the blood brain barrier (BBB). These two critical functions require the coordinated activity of a neurovascular unit that includes perivascular neurons, astrocytes, endothelial cells, and vascular smooth muscle cells. There is some experimental evidence that dysfunction of the neurovascular unit may be an early event in AD (AD).1 The functional organization of the neurovascular unit and its possible role in the pathogenesis of AD have been discussed in detail in several excellent reviews.1,2,3,4 Neurovascular mechanisms in AD may have important implications for the prevention of neuronal loss in this disorder. The coupling between neuronal activity and regional CBF is referred to as functional hyperemia.1,2 Functional hyperemia is triggered primarily by increases in synaptic activity, with a contribution of metabolic signals resulting from increased energy consumption by active neurons and astrocytes. This activity-related increase in CBF is due to the release of several vasodilator substances from perivascular neurons, astrocytes, and endothelial cells. These include extracellular potassium (K+) and hydrogen (H+) ions, adenosine, nitric oxide (NO), prostanoids, and neurotransmitters released from perivascular neuronal processes.1,2,3,5,6 Glutamate, which is released from active excitatory synapses, is not vasoactive but stimulates the release of NO, prostaglandins, and other vasodilator substances from target neurons and astrocytes (figure). Figure Some of the proposed mechanisms of functional hyperemia in response to excitatory synaptic activity Glutamate (Glu), released from excitatory synapses, activates NMDA (NMDA) receptors in neurons and metabotropic glutamate receptors (mGluR) in perisynaptic astrocytes. This results in increase in cytosolic levels of calcium (Ca2+), which triggers the production and release of several vasodilator substances from these cells. For example, Ca2+ stimulates phospholipase A2 …