# Exploration of a Novel Therapeutic for Alzheimer's Disease and Related Disorders

> **NIH NIH F99** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2022 · $8,244

## Abstract

“Exploration of a Novel Therapeutic for Alzheimer’s Disease and Related Disorders”
Project Summary / Abstract
Neurodegenerative disorders are responsible for progressive loss of synaptic function that is accompanied by
cognitive decline. The mechanisms in which pathological hallmarks of these diseases influence the functioning
of cognitive processes such as memory recognition, planning, and decision making, is a major focus for
therapeutic research. In Alzheimer’s disease (AD), the primary pathological marker thought to be most closely
linked to cognitive dysfunction is neurofibrillary tangles (NFTs), which are comprised of pathogenic aggregates
of hyperphosphorylated tau. To better understand the pathophysiological relationship between synaptic loss and
cognitive dysfunction in a tau model for AD and related disorders (ADRD), the transgenic mouse model P301S
which overexpresses hyperphosphorylated tau was employed for this project. Work done during my predoctoral
studies revealed a decline of proper spatial and short-term recognition memory that is accompanied by the
progressive loss of the glutamatergic receptor NMDAR and NMDAR transmission in prefrontal cortex (Aim 1). It
is suspected that maladaptive pathophysiological mechanisms associated with the onset of NFTs are
responsible for synaptic and cognitive dysfunction. An area of interest is the ubiquitin-proteasome system (UPS),
a clearance mechanism responsible for protein degradation in the cell. Defective protein clearance has been
implemented in AD, however the role in which the UPS relates to tau-induced cognitive decline has yet to be
elucidated. Further preliminary data identified the upregulation of an E3 ubiquitin ligase to be responsible
abnormal degradation of NMDARs. In Aim 2 I will determine if selectively knocking down this E3 ubiquitin ligase
in PFC of P301S mice through in vivo gene transfer will rescue synaptic and cognitive dysfunction. This will be
assessed through cognitive behavioral assays, biochemical and immunocytochemical detection of synaptic
proteins, and electrophysiological recordings. These highly transferable skills will allow me to transition into a
postdoctoral appointment, where I aim to study how epigenetic enzymes direct chromosomal architecture,
causing downstream changes in gene expression seen in neurodegenerative disorders (Aim 3). My long-term
goal is to obtain a faculty position at a research-intensive institution where I will combine a multifaceted approach
in understanding how the spatial organization of chromatin can lead to neurobiological and neurodegenerative
etiologies.

## Key facts

- **NIH application ID:** 10334479
- **Project number:** 5F99NS118745-02
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Jamal Williams
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $8,244
- **Award type:** 5
- **Project period:** 2021-01-02 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334479

## Citation

> US National Institutes of Health, RePORTER application 10334479, Exploration of a Novel Therapeutic for Alzheimer's Disease and Related Disorders (5F99NS118745-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10334479. Licensed CC0.

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