Thursday, April 25, 2024
4/25/2024
PROJECT SUMMARY AND ABSTRACT: Alzheimer's disease and related dementias (ADRD) are disabling conditions that progressively deprive affected individuals of their cognitive functions, ultimately leading to their inability to perform basic activities of daily living. The brain depends on continuous and well-regulated delivery of energy substrates through the brain blood flow, which is accomplished by elaborate neurovascular control mechanisms that always ensure sufficient cerebral perfusion. One such mechanism, termed functional hyperemia, couples local neural activity with the delivery of blood flow and requires tissue plasminogen activator (tPA) for its full expression, since tPA enables the production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. Neurovascular alterations are observed early in the disease course of ADRD and may promote the expression of cognitive impairment. Amyloid-beta, a significant pathogenic contributor to AD, suppresses functional hyperemia by upregulating the tPA inhibitor PAI-1 resulting in a reduction in tPA activity. However, the cellular sources of PAI-1 remain unclear, and their identification would suggest new approaches to rescue the neurovascular dysfunction induced by amyloid- beta. Perivascular macrophages (PVM), brain resident myeloid cells distinct from microglia located in the perivascular space, can produce large amounts of reactive oxygen species (ROS) which are critical drivers of PAI-1 upregulation. Therefore, we will test the central hypothesis that PVM are the major source of the PAI-1 that leads to tPA deficiency, neurovascular dysfunction, and cognitive deficits induced by amyloid-beta. This hypothesis will be tested in 3 specific aims: (1) PVM are the source of PAI-1 mediating tPA deficiency and neurovascular uncoupling induced by amyloid-beta, (2) PVM CD36 and Nox2, which are responsible for the ROS production in these cells, mediate the PAI-1 upregulation, and (3) PVM PAI-1 contributes to the effects of long-term accumulation of amyloid-beta. These specific aims will be accomplished by employing tour de force approaches, including in vivo and in vitro techniques. The application will widen our knowledge basis for the cellular mechanisms of harmful neurovascular effects of amyloid-beta.
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