# Neuroinflammation and developmental vulnerability to manganese toxicity

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2022 · $323,735

## Abstract

Project Summary – supplement application
Studies over the past two decades have cast doubt on the amyloid seeding hypothesis of Alzheimer’s disease
(AD), noting that early changes in microglia morphology and reactivity precede deposition of amyloid beta
(Aβ) in affected brain regions. Moreover, these cellular changes occur prior to the appearance of Aβ
plaques. In addition, the most significant risk factors for development of AD include genes variants
associated with innate immunity in microglia, such as TREM2 and APOE4. These findings and others
suggest an environmental link to early pathological changes in AD-sensitive brain regions associated with
activation of innate immunity in glial cells. Environmental pesticides are one class of agents known to
increase risk for AD. Many of these agents share a common mechanism in causing mitochondrial
dysfunction and activation of inflammatory gene expression in microglia and astrocytes. However, the
molecular signals regulating innate immune pathways in microglia in response to environmental pesticides
are not well understood, particularly with respect to complex temporal changes in microglia phenotype
associated with inflammation and autophagy in response to Aβ and Tau misfolding. The basis for this NOT-
AG-21-018 Alzheimer’s-focused supplement application is the striking discovery from the parent research
project in rotenone-treated mice of significant levels of alpha-synuclein protein aggregation in the
hippocampus and entorhinal cortex, both regions affected in AD. Upon further interrogation of these brain
regions, we found increased levels of both phosphorylated Tau (P-Tau) and Aβ, neither of which have been
previously described in response to rotenone treatment in mice. Given that rotenone is a systemic inhibitor
of mitochondrial complex I that is commonly used to model the effects of diverse pesticides affecting
mitochondria, this raises the exciting possibility of a better model for the metabolic and neuroinflammatory
derangements seen in AD that could be explored using powerful transgenic tools in mice. It is the central
hypothesis of this supplement application that rotenone-dependent mitochondrial dysfunction causes
activation of innate immune inflammatory signaling pathways in microglia that promote aggregation of Aβ
and Tau in neurons, as well as amplifying astrocyte reactivity that contributes to neuroinflammation and
cognitive decline. This hypothesis will be explored during the one-year supplement project period through
the following two focused and complementary Specific Aims: Specific Aim 1 - Determine the spatio-
temporal sequence of glial activation and aggregation of Aβ and Tau in mice exposed systemically to
rotenone. Specific Aim 2 - Identify mechanisms by which rotenone enhances inflammatory activation of
microglia and autophagy of Aβ+ and Tau+ protein aggregates. The rotenone mouse model developed in the
parent research project and used in this supplement application shows chang...

## Key facts

- **NIH application ID:** 10499687
- **Project number:** 3R01ES021656-10S1
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** RONALD TJALKENS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $323,735
- **Award type:** 3
- **Project period:** 2018-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499687

## Citation

> US National Institutes of Health, RePORTER application 10499687, Neuroinflammation and developmental vulnerability to manganese toxicity (3R01ES021656-10S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10499687. Licensed CC0.

---

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