Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the leading cause of dementia in adults over the age of 65, and currently affects approximately 6.5 million people in the United States. By 2050, the number of people age 65 and older with AD dementia is projected to reach 12.7 million, barring the development of medical breakthroughs to prevent, slow or cure AD. Thus, there is a need for progress in the understanding of AD pathophysiology, as well as in development of effective therapeutics. Notably, 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. 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 older 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 relationship between dendritic spine loss and cognitive impairment in AD. Towards this goal, I implemented an integrative mass spectrometry (MS)-based proteomic strategy for the nomination and validation of proteins associated with cognitive resilience to AD. Correlation network analysis across distinct stages of AD was used to prioritize protein modules linked to resilience. Neuritin-1 (NRN1) was identified as a top candidate of resilience in a module associated with synaptic biology. My published findings revealed that NRN1 provided dendritic spine resilience against Aβ and blocked Aβ-induced neuronal hyperexcitability. Moreover, NRN1 treatment induced changes in the neuronal proteome related to broad synaptic functions. 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. In order to support the promise of NRN1 as a therapeutic target in AD, it is critical to determine whether NRN1 can suppress neuronal injury that is induced by pathologic tau. In my network analysis of resilient patients, I identified that NRN1 protein abundance is positively correlated with cognition and inversely correlated with NFT density and Braak Stage. Collectively, this suggests that NRN1 may influence tau pathology or that tau pathology may influence NRN1 levels. The goal of this proposal is to further understand cognitive resilience at the synapse and test the hypothesis that NRN1 enhances structural plasticity of dendritic spines to protect synapses from the degenerating forces of tauopathy in AD. Aim 1 will determine if NRN1 prevents dendritic spine degeneration and cognitive deficits in tauopathy mice. Aim 2 will determine whether NRN1 is protective against synaptic dysfunction induced by pathologic tau. Collectively, findings from the proposed project will inform on the role of NRN1 as a molecular mediator of cognitive resilience to AD neuropathology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).