Advisor(s)

Jeremy Herskowitz

Committee Member(s)

Ashley Harms
Briana De Miranda
Erik Roberson
Jeremy Day

Document Type

Dissertation

Date of Award

1-27-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Joint Health Sciences

Abstract

Alzheimer’s disease (AD) is the leading cause of dementia in adults over the age of 65, and currently affects approximately 6.9 million people in the United States. By 2060, the number of people age 65 and older with AD is projected to reach 13.8 million, barring the development of disease-altering therapies to prevent, slow or cure AD. Thus, there is a need for progress in the understanding of AD pathophysiology, as well as in the development of diagnostic and therapeutic interventions. Approximately one-third of individuals without dementia at the time of death are found to harbor high levels of amyloid-beta (Aβ) and tau neurofibrillary tangle (NFT) pathology. Individuals that evade cognitive de-cline despite high levels of Aβ and NFT pathology appear to exhibit cognitive resilience to the clinical manifestations of AD. Dendritic spine loss correlates more strongly with cognitive impairment than AD neuropathology. Dendritic spine plasticity is hypothesized to be a mechanism of cognitive resilience that protects individuals with moderate to severe AD neuropathology from developing dementia. It is therefore important to identify genes and proteins that mediate cognitive resilience in order to understand the relation-ship between dendritic spine loss and cognitive impairment in AD. Here, we implemented an integrative mass spectrometry (MS)-based proteomic strategy across distinct stages of AD to prioritize protein modules linked to resilience. Computational strategies identified Neuritin-1 (NRN1) as a top candidate of resilience in a module associated with synaptic biology. The established link between synaptic loss and cognitive impairment in AD and the predominance of synaptic proteins in our top resilience-associated modules, warrants examining the impact of NRN1 on synaptic integrity and maintenance as foundational to determining NRN1’s role in resilience. To validate the computational analysis, primary cultured neurons were used to evaluate the neuroprotective mechanisms of NRN1 against Aβ. To advance the investigation of NRN1 as a therapeutic target candidate for AD, we characterized commercially available polyclonal NRN1 antibodies using in vitro and in vivo models systems as well as postmortem human brain tissue samples. This work furthers our understanding of NRN1 as a molecular mediator of cognitive resilience to AD neuropathology.

Keywords

Aging;Alzheimer’s disease;Cognition;Neurotrophic factor;Proteomics;Resilience

ProQuest Publication Number

32238278

ISBN

9798273349346

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