2023 Alzheimer's Association Research Fellowship (AARF)
Elucidating the Proteinopathic Drivers of Network Dysfunction in AD
Can an ultrasound-based technology reveal why nerve cell communication across brain regions declines in Alzheimer’s?
Samuel Harris, Ph.D.
University College London
London, United Kingdom
Background
Nerve cells in different brain regions communicate with each other via nerve cell networks (circuits) that connect the regions. These networks help control memory and other cognitive functions. According to many studies, brain changes in Alzheimer’s, such as the accumulation of beta-amyloid and tau protein, may be associated with disease-related changes in network-to-network communication (or “functional connectivity”). Scientists, however, do not yet understand the biological mechanisms underlying these associations. Part of the reason for this knowledge deficit is that researchers have lacked scanning tools that can accurately visualize the complex interactions between networks across the brain.
In initial studies, Dr. Samuel Harris and colleagues have been experimenting with fUSI (functional ultrasound imaging), a novel brain scanning method that uses ultrasound technology to visualize brain network connections. With this method, they found that genetically engineered Alzheimer’s-like mice with high beta-amyloid levels in their brain showed increased functional connectivity. In mice with high levels of both amyloid and tau, however, the rodents showed reduced connectivity. These findings confirmed the work of other recent studies, which revealed that network connectivity becomes abnormally increased by beta-amyloid in the earliest stages of Alzheimer’s; and then, when tau protein begins to accumulate, connectivity gradually declines – a process that eventually leads to cognitive decline in dementia.
Research Plan
Dr. Harris and colleagues will expand on their initial study to utilize fUSI and Alzheimer’s-like mice with either beta-amyloid or beta-amyloid and tau in their brains. First, they will look to clarify how functional connectivity is altered by beta-amyloid and tau. Next, the researchers will identify molecular mechanisms underlying these protein-related changes, such as how tau accumulation may hinder the activity of synapses (the structures in between brain cells through which cells send chemical signals to communicate). Lastly, Dr. Harris and team will examine whether reducing beta-amyloid and/or tau clumping can restore normal functional connectivity in the mice.
Impact
The results of this study shed new light on the complex ways beta-amyloid and tau impact nerve cell communication throughout the brain in Alzheimer’s. They could also identify fUSI as a potential technology for diagnosing and monitoring Alzheimer’s in humans.