# Impact of pesticide exposure on mechanisms of neuroplasticity in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $397,500

## Abstract

PROJECT SUMMARY
Alzheimer’s disease is the most common age-related neurodegenerative disorder with ~5.4 million Americans
living with Alzheimer’s disease. Central to Alzheimer’s disease is the ongoing loss of neuronal plasticity which
impairs cognitive functions and eventually disrupts basic brain functions, resulting in death. Yet, we still lack
significant disease-modifying interventions for the disease. Thus, new approaches are needed to identify the
mechanisms involved in Alzheimer’s disease pathogenesis. Key clues come from evidence that exposures to
environmental neurotoxicants are causally linked to a higher incidence of Alzheimer’s disease. Moreover, there
are sex differences in Alzheimer’s disease with women more affected compared to men. Finally, one of the most
salient consequences of Alzheimer’s pathology is the loss of neuroplasticity and neurodegeneration, which
strongly correlates with memory loss as well as cognitive and motor decline. Together, these findings extend our
existing NIEHS-funded R01 (R01ES034037) whose focus is to investigate mechanisms by which the vesicular
glutamate transporter 2 (VGLUT2) mediates selective vulnerability to neurodegeneration in males and females
caused by exposure to environmental toxicants including pesticides. To adapt the core concepts of our R01 to
Alzheimer’s disease, we established an experimental system where we can convert human fibroblasts from
Alzheimer’s disease patients and age-matched unaffected individuals directly into induced neurons (iNs). This
approach enables the iNs to retain the epigenetic and transcriptomic age signatures similar to those of the aging
human brain and has proven vital for modeling the pathology for age-related neurodegenerative disorders like
Alzheimer’s disease. Critically, we can generate several unique patient-derived iNs of sporadic and familial
Alzheimer’s disease from male and female patients, enabling us to recapitulate key aspects of human
Alzheimer’s disease pathophysiology. In parallel, we developed new live-cell and cryo-electron tomography
approaches in primary neurons and iNs to study activity-driven local translation – a process that is central to
synaptic plasticity and which is lost in Alzheimer’s disease. In this supplement, we will take advantage of
innovative new tools and our team’s expertise in neurodegeneration to answer several fundamental questions:
1) whether pesticides exacerbate mitochondrial oxidative stress in Alzheimer’s disease patient neurons to
increase Alzheimer’s pathology (e.g., amyloid-b and tau accumulation) and accelerate cell loss; 2) if pesticide
exposures impact mitochondrial function and cell plasticity differently in male vs female Alzheimer’s iNs; and 3)
if modifying VGLUT2 expression alters pesticide-induced neurodegeneration in male vs female Alzheimer’s
patient iNs. We hypothesize pesticide-induced mitochondrial dysfunction initiate or exacerbate accumulation of
pathological hallmarks of Alzheimer’s disease, culm...

## Key facts

- **NIH application ID:** 10938478
- **Project number:** 3R01ES034037-02S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ZACHARY FREYBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $397,500
- **Award type:** 3
- **Project period:** 2023-03-06 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938478

## Citation

> US National Institutes of Health, RePORTER application 10938478, Impact of pesticide exposure on mechanisms of neuroplasticity in Alzheimer's Disease (3R01ES034037-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10938478. Licensed CC0.

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