Alzheimer's Diseases?the most common cause of dementia in aging adults?is a slow, but progressive, deterioration of the brain that leads to neurodegeneration and cognitive impairment. The classic neuropathological sign of the disease is the accumulation of amyloid-?-containing plaques, which can lead to neuronal damage when free amyloid-? oligomers form Ca2+-permeable pores, cause membrane permeabilization and neuronal cell death. More recently, cardiovascular pathologies have been implicated in the progression of Alzheimer's Disease and other forms of dementia. However, how these pathologies contribute to the pathogenesis of Alzheimer's Disease is poorly understood; how vascular dysfunction potentiates the failure to clear toxic amyloid-? from ageing brains. Our recent work provides evidence that capillaries?the smallest vascular conduits and the point of nutrient delivery and waste removal between blood and surrounding neurons ?act as a sensory network that detects and responds to neural activity by promoting an increase in local blood flow (functional hyperemia). In addition, we observe that contractile pericytes maintain the efficiency of network perfusion by controlling blood flow at capillary junctions. In Preliminary Results, we provide new evidence that amyloid-? peptide, the major constituent of amyloid plaques in the brains of Alzheimer's patients, increases the frequency of Ca2+ events in contractile pericytes, but not in nearby vascular smooth muscle cells. This has led us to speculate that amyloid-? peptide-mediated increases in the frequency of Ca2+ events interrupt normal pericyte Ca2+ signaling, leading to Ca2+ overload and cell death, and disruption of pericyte-mediated control of junctional blood flow. With the support of this COBRE application, we propose to test our overarching hypothesis that the progressive loss of pericyte function at capillary junctions reduces the efficiency of capillary network perfusion, ultimately affecting the health and function of surrounding neurons.
The aims of the current study are 1) to elucidate the molecular mechanisms underlying amyloid-? peptide-induced increases in pericyte Ca2+ events; and 2) to elucidate the pathophysiological effects of amyloid-? on junctional pericyte control of local and global blood flow. Successful completion of these studies is expected to provide insights into how amyloid-? peptide accumulation disrupts blood flow within the microenvironment to negatively impact neuronal vitality, and to provide therapeutic targets for the prevention of the neurodegeneration that leads to cognitive impairment and dementia.
