Declines in Neuron-Vasculature Crosstalk as a Cause of Alzheimer’s Disease

The goal of this project is to identify novel neurovascular interaction pathways that may be ultimately useful for improving clinical Alzheimer’s outcomes. All neural function depends on an adequate energy supply from the vasculature. This process is called neurovascular coupling, and changes to neuron driven blood flow are one of the earliest pathological events in Alzheimer’s disease. Based on our preliminary data, we hypothesize that changes to pericyte driven neurovascular coupling accelerate neural decline in AD. Specifically, we will: (1) determine the structural and functional mechanisms by which AD regulates vascular and pericyte integrity; and (2) define the cell-specific molecular pathways involved in vasculature dysfunction in AD.

Alzheimer’s disease (AD) affects millions of individuals, and co-morbities such as vascular disease can significantly accelerate cognitive decline. Our work and others suggests that alterations to neuron and blood vessel communication may drive these outcomes. In this study, we aim to understand how AD disrupts energy homeostasis and neurovascular coupling through specialized vascular structures called pericyte nanotubes. These approaches may open new therapeutic avenues for slowing AD progression and improving cognitive function over time.

This proposal is innovative in several regards. First, we address a large unanswered question- whether and how neurovascular coupling influences AD progression. Second, we focus on a novel component of the vasculature, inter-pericyte tunneling nanotubes (IP-TNTs). Third, we have developed technically innovative approaches that that allow us to visualize neuron and vessel interactions. These include new nanoscopic imaging methods we RAIN-STORM and a novel high-throughput sequencing paradigm called STATE-Seq that allows us to isolate and neurons and pericytes in defined intracellular states

The goal of this proposal is to map the drivers of AD mediated declines in neurovascular coupling. Solving this mystery is key to preventing AD pathogenesis because: 1) vascular abnormalities occur early in disease, 2) vascular risk factors exacerbate cognitive decline in AD patients; and 3) the vasculature itself is a target of amyloid deposition. In addition, improved cerebrovascular health can reduce AD progression. These studies will define the role of neurovascular coupling AD and may identify new therapeutic targets for mitigating AD-related declines to cognitive function.