Date of Award

9-12-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Information Science

First Advisor

Robert Shmookler Reis

Second Advisor

Srinivas Ayyadevara

Abstract

Cardiovascular disease (CVD) is the leading cause of death in the world and in the United States. Reduced cardiac output due to CVD has been previously associated with decreases in systemic and cerebral perfusion. Cerebral hypoperfusion increases the risk of Alzheimer’s disease (AD), accompanied by accumulation of aggregates that feature Aβ amyloid and hyperphosphorylated tau. Protein aggregation is a shared hallmark of aging and neurodegenerative diseases. We previously reported elevated aggregation in hearts of hypertensive and aged mice and now find that aggregation is induced in hearts and brains of male C57BL/6 mice after transient ligation of the left coronary artery, modeling natural myocardial infarction (MI). We also show increased endoplasmic reticulum (ER) stress in both heart and brain of these mice after MI. We carried out aggregate crosslinking studies in brain tissues of age-matched control (AMC), Alzheimer’s disease (AD) and heart disease (HtD) individuals using a click-chemistry protocol. AD brains had elevated aggregate interactions relative to AMC. Interestingly, although HtD aggregates have complexity (interaction levels) similar to AMC, aggregation of critical proteins involved in neuro¬degeneration pathways such as those comprising the ubiquitin proteasome system (UPS), mitochondria, and ER are present in HtD and AD aggregates at similar levels, but not in AMC. This suggests that heart disease might predispose proteins in the brain to aggregate, leading to conditions favoring cognitive decline, eventually leading to AD. In addition, knockdown of RNAs encoding these proteins reduced aggregation in a neuroblastoma cell line (SY5Y-APPSw). By screening the binding interface between amyloid β-peptide (Aβ) and one of its direct contacts in aggregates, voltage -dependent anion channel 1 (VDAC1), we discovered small molecules that can inhibit their interaction, reduce hypoxia-induced insoluble aggregates in SY5Y-APPSw cells, decrease Aβ load in C. elegans neurons, and reverse the disrupted mitochondrial membrane potential.

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