The impact of reduced blood flow early in Alzheimer's disease on neuronal function.

PROJECT SUMMARY Alzheimer's disease is the leading cause of dementia in the elderly and has been identified by the NIH as a research priority. Although it is well known that vascular health is impaired in Alzheimer's disease, we still lack a full understanding of how this impacts neural function as the disease develops. Indeed, one of the major debates in the field of Alzheimer's research is whether breakdowns in vascular activity are contributing to the accompanying neurological disorders seen in Alzheimer's disease or are merely an additional symptom. In this proposal we will study how reduced flow early in Alzheimer's disease impacts neuronal function. In Aim 1, we will use two-photon fluorescence microscopy to characterize the neuronal and vascular response alterations in a mouse model of Alzheimer's disease with high spatial and temporal detail. We will analyze changes in response amplitude, latency, and selectivity, and in the number of responsive neurons and vessels. We will focus on the timing of the appearance of neuronal and vascular response alterations to determine if they appear at the same point in disease progression or if blood flow reductions can exist without detriments to neuronal activity. Furthermore, the limited metabolic resources provided by reduced blood flow may be consumed by neurons closer to capillaries before reaching neurons farther away. Therefore, we will also determine if the distance from neurons to the nearest vessel correlates with earlier or more pronounced neuronal dysfunction. Our ability to record from hundreds of neurons and vessel segments in small volumes of cortex with single-cell/single-vessel resolution will give us unprecedented detail into the functioning of the neurovascular unit in the early stages of disease progression. In Aim 2, we will use two-photon optogenetics and a novel mouse line to test the effects of reducing blood flow during functional hyperemia in Alzheimer's disease. We are currently testing how reducing or eliminating the increase in blood flow following sensory stimulation alters neural activity in normal animals. Here we will apply the same manipulation in AD animals to determine if the reduced blood flow seen early in the disease leaves the neurovascular unit more susceptible to altered blood flow than in normal animals. Healthy tissue may be able to cope with moderate reductions in the sensory-evoked hyperemic response more robustly than neurons in Alzheimer's brains. Understanding the vulnerability of the neural tissue to blood flow reductions in Alzheimer's disease will help shed light on how vascular risk factors contribute to enhanced disease pathology. We will use sensory stimuli to activate tissue and then restrict the dilation of arteries and analyze responses in the same way as in Aim 1, comparing response alterations in Alzheimer's animals with healthy controls. The results from these experiments will provide a more complete picture of the link between neural and vascular dysfunction early in Alzheimer's disease and guide future vascular-based therapies.