# Mechanistic studies of synaptopathies associated with Alzheimer's risk factors

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $190,625

## Abstract

PROJECT SUMMARY/ABSTRACT
One of the earliest changes in Alzheimer’s Disease (AD) is dysfunction of synaptic transmission, thus
interfering with information processing by neuronal networks. However, despite intensive study, the factors
contributing to synaptic dysfunction, and thus cognitive decline, are not understood. Thus, it is of fundamental
importance to understand how candidate genes implicated in AD such as amyloid precursor protein (APP) and
superoxide dismutase (SOD) disrupt synaptic signaling. The scientific premise of the current proposal is to
generate animal models of AD and undertake a genetics-based, systems biology approach to gain a
fundamental understanding of how AD changes neuronal function(s). In contrast to complementary efforts in
other systems, what distinguishes the current proposal is single neuron resolution, a focus on real-time in vivo
intracellular transport of synaptic receptors and APP, and a systematic effort to discover regulatory,
homeostatic and gene expression pathways that control or modify synaptic receptors and neurotransmission.
We have modeled the overexpression of SOD and APP in transgenic C. elegans to gain new insights into the
pathophysiology of AD. In preliminary experiments, we observed striking disruption of synaptic function in
transgenic worms that overexpressed either SOD-1 or APL-1 (C. elegans homologs of SOD and APP,
respectively). In particular, we found that motor-mediated transport of AMPA-type ionotropic glutamate
receptors and glutamate-gated currents were severely disrupted, leading to altered behavior of the animals.
These results provide a new conceptual framework for investigating the pathophysiology of synaptic
dysfunction in AD.
In this proposal, we test mechanistic models of SOD-1 and APL-1 mediated disruption of synaptic function, and
we outline a strategy to identify novel genetic modifiers that restore synaptic transmission in our transgenic
models of AD. Because of evolutionary conservation of APP, SOD, synaptic proteins, microtubule-dependent
motors and most intracellular signaling pathways, our studies will have immediate relevance to the
pathophysiology of AD in humans. Additionally, we expect our studies will provide new therapeutic strategies,
and entry points for the treatment of AD and other neurodegenerative disorders associated with APP and SOD.

## Key facts

- **NIH application ID:** 9980770
- **Project number:** 5R21AG064406-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Andres Villu Maricq
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980770

## Citation

> US National Institutes of Health, RePORTER application 9980770, Mechanistic studies of synaptopathies associated with Alzheimer's risk factors (5R21AG064406-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9980770. Licensed CC0.

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