# The Role of Synaptic Proteolysis in Alzheimer's Disease and Therapeutic Implications

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $583,195

## Abstract

Tau-containing neuronal inclusions are a prominent feature of Alzheimer’s disease (AD), frontal temporal
dementia (FTD) and other disorders with tauopathy, implying a deficit in the cell’s ability to clear misfolded tau
species either as a cause or a consequence of the disease process. Tau is a substrate of the ubiquitin
proteasome system (UPS), thus elucidating mechanisms how proteasome becomes dysfunctional in tauopathy
may identify pathways that could be targeted therapeutically. Synaptic dysfunction, which is thought to be an
early pathological manifestation in AD and other tauopathies, is associated with abnormal missorting and
accumulation of tau in synapses. And recent evidence suggests that pathogenic progression in synapses in AD
correlates with accumulation of ubiquitinated proteins in synaptic fractions, suggesting UPS dysfunction.
Here we propose that missorted tau in synapses disrupts proteasomal activity contributing to broader synaptic
toxicity. We hypothesize that one of the consequences of tau-induced impaired synaptic proteolysis is sustained
tetrameric (inactive) conformation of PKA holoenzyme and downregulation of CREB transcription signaling, an
important pathway related to synaptic plasticity and memory.
The goal of AIM 1 is to examine whether there is a relationship between accumulation of pathological tau in pre
and post -synaptic compartments, the function of synaptic proteolysis and the status of PKA/CREB signaling
using brain tissue from AD, FTD and normal brains. Examination of the synaptic distribution of tau species in the
pre and post synaptic compartment and its competency to seed and propagate will enable us to identify the
biochemical signature of synaptic tau in two tauopathies. In an effort to identify mechanisms that contribute to
synaptic toxicity, AIM 2 will test in a series of in vitro assays using primary neurons and microfluidic-based cell
model of fluidically isolated synapses, whether accumulation of tau aggregates throughout the cell or in synapses
(during trans-synaptic propagation), can elicit a negative effect on the PKA/CREB signaling due to impaired
proteasome clearance mechanism. As a therapeutic strategy, AIM 3 will investigate if stimulation of Gs-coupled
GPCR, situated on the synaptic terminals, rescues/activates cAMP/PKA pathway leading to increased
proteasome proteolysis of tau species in synapses. The application of a therapeutic strategy of receptor-
stimulated proteolysis with spatially defined mechanism of action for effective tau clearance, can identify a new
mechanism to halt missorting of tau and subsequent trans-synaptic spread. Targeting GPCR signaling as a
strategy to activate proteasome mediated proteolysis can have a significant impact in finding new drugs for
proteinopathy diseases.

## Key facts

- **NIH application ID:** 10388124
- **Project number:** 5R01AG064244-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Natura Myeku
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $583,195
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388124

## Citation

> US National Institutes of Health, RePORTER application 10388124, The Role of Synaptic Proteolysis in Alzheimer's Disease and Therapeutic Implications (5R01AG064244-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10388124. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*