Advisory Committee Chair
Erik Roberson
Advisory Committee Members
Jeremy Day
Jorge Palop
Jacques Wadiche
Lori L McMahon
David Standaert
Document Type
Dissertation
Date of Award
2020
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Alzheimer’s disease (AD) is the leading neurodegenerative disorder that affects an astonishing 5.8 million Americans, a number projected to reach 14 million by the year 2050. While only about 1% of all AD cases are caused by mutations in APP, PSEN1, and PSEN2, the cause of sporadic AD remains unknown. Variations in several risk genes have been proposed to contribute to the development of sporadic AD cases. Since, currently, there are no disease-modifying therapies for families affected by AD and multiple anti-amyloid-beta therapies failed in clinical trials, determining how these risk genes contribute to the development of AD is crucial to identify new therapeutic avenues in AD. The second leading generic risk after APOE is BIN1, a direct interacting partner of Tau. Based on considerable preclinical data from AD models, genetically reducing either Tau or reducing its interaction with its binding partners has beneficial effects relevant to AD. Here, we describe BIN1’s role in neurons and how its interaction with Tau regulates network hyperexcitability through a voltage gated calcium channel complex. Furthermore, we characterized BIN1’s isoform-specific expression profiles in the human brain and its changes in the AD brains. Lastly, we determined that the loss of BIN1 in the brain leads to network hyperexcitability. Together, these data provide new insight into the potential role BIN1 plays in AD pathophysiology.
Recommended Citation
Voskobiynyk, Yuliya, "Tau-Dependent Regulation Of Network Hyperexcitability By Alzheimer’S Disease Risk Gene Bin1" (2020). All ETDs from UAB. 703.
https://digitalcommons.library.uab.edu/etd-collection/703