Advisor(s)
Jeremy Herskowitz
Committee Member(s)
Alexa Mattheyses
Ashley Harms
Cristin Gavin
Erik Roberson
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
9-11-2025
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia in individuals over the age of 65. Amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) are the pathological hallmarks of AD, yet synapse and dendritic spine loss show a stronger correlation with cognitive impairment. Emerging evidence suggests that Rho-associated coiled-coil kinase 2 (ROCK2) is a regulator of dendritic spine structure, making it a promising therapeutic target for synapse preservation in AD. Beyond synapse loss in AD, synaptic connections likely facilitate the spread of pathological tau to anatomically connected brain regions. It has been proposed that pathologic tau can act as a “prion-like” seed which can drive misfolding and aggregation of physiological tau. Therefore, tau seeds residing in synaptic compartments may be crucial to the spread or propagation of tau. This dissertation explores two aspects of synaptic dysfunction in AD: the role of ROCK2 in regulating dendritic spine density and morphology, and the bioactivity of synaptic tau seeds in relation to cognition and neuropathology. The first project utilized a ROCK2-depleted mouse model to investigate ROCK2’s impact on behavior and dendritic spine structure. We determined that ROCK2 mediates spine density and morphology among CA1 pyramidal cells and may contribute to anxiety-like behaviors. The second project aimed to determine whether relationships exist between synaptic tau seed bioactivity and cognitive or neuropathological data. To investigate this, inferior temporal gyrus (ITG) synaptosomes were prepared from 128 Religious Order and Rush Memory and Aging Project (ROSMAP) postmortem tissue samples. We detected synaptic tau seed bioactivity from cases at high Braak stages, but little to no bioactivity from early Braak stages. Synaptic tau bioactivity was inversely correlated with episodic, semantic, and working memory scores. NFT and Aβ pathology scores were positively correlated with synaptic tau seed bioactivity. Synaptic tau seed bioactivity was integrated with multiplex tandem mass tag mass spectrometry (TMT-MS) ITG proteomics. Proteome analysis uncovered protein signals associated with molecular pathways that may underlie synaptic tau seed bioactivity. Collectively, this work furthers our understanding of synaptic structure mediated by ROCK2 and synaptic tau seeding in AD.
ProQuest ID
Recommended Citation
Weber, Audrey, "Structural And Molecular Alterations At The Synapse In Alzheimer'S Disease" (2025). All ETDs from UAB. 7356.
https://digitalcommons.library.uab.edu/etd-collection/7356
