Tuesday, April 1, 2025
4/1/2025
The Role of Alzheimer's Disease Risk Genes in Neural Function, Degeneration, and Synapse Organization - PROJECT SUMMARY As the population ages, the proportion suffering from neurodegenerative diseases is projected to nearly double over the next 30 years. Alzheimer’s Disease (AD) represents one of the most common neurodegenerative diseases, but the mechanisms that underlie AD remain incompletely understood. Despite considerable research and investment, no effective treatments exist for AD and though mutations in many AD genes have been discovered, understanding how they contribute to the disease has also been challenging. Specifically, mutations in PSEN1, which encodes Presenilin, the catalytic subunit of the protease γ-secretase, are conclusively linked to early-onset familial Alzheimer’s Disease; impaired PSEN1 function results in Aβ accumulation due to incorrect cleavage of amyloid precursor protein. Though Aβ accumulation is a pathological hallmark of Alzheimer’s Disease, it is unknown how such an accumulation influences Alzheimer’s Disease progression. Such an uncertainty points towards a need for new avenues of research, specifically to determine the normal biological roles of genes associated with AD and understand how perturbations in synapse biology lead to cognitive impairment. Our prior work identified a novel role for Presenilin (and γ-secretase) in synaptic maturation, a normal process that is essential for synapses to progress from nascent, newly formed connections to robust, plastic entities. However, the connection between PSEN1 mutations linked to AD and adult synapse biology, remains unclear. Using two new models of patient-identified PSEN1 mutations that cause defects in synaptic maturation, we will first examine how these heterozygous dominant (and homozygous) mutations influence adult neurodegeneration in the central brain and whether these mutations induce behavioral deficits associated with AD. Subsequently, we will examine whether these PSEN1 mutations influence central synapse formation in the olfactory system. In neurodegenerative diseases like AD, olfactory symptoms often precede those of memory loss, so understanding how mutations linked to AD affect smell is paramount. We will determine if these mutations, the first in vivo inductions of Alzheimer’s causing mutations into the endogenous Drosophila gene, impair active zone formation. We will also test whether Wnt signaling, the pathway involved in presenilin- dependent synaptic maturation at peripheral synapses, is also involved in central synapse biology. Taken together, this proposal will greatly enhance our understanding of the shared mechanisms of synaptic maturation, determine how Alzheimer’s related mutations influence neurodegeneration, and begin to connect a novel biological role for Presenilin with the molecular mechanisms underlying Alzheimer’s Disease. Together, this data will provide new insight into gene function and may offer ameliorative strategies for Alzheimer’s Disease.
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