# Investigating the functional consequences of seeding in mammalian primary neurons with Alzheimer’s Disease brain-derived tau filaments

> **NIH NIH F31** · MICHIGAN STATE UNIVERSITY · 2022 · $38,942

## Abstract

Project Summary/Abstract
The prevalence of Alzheimer’s disease (AD), a progressive neurodegenerative disease, continues to increase
at a staggering rate. Current AD therapies provide modest symptomatic relief, creating a need for disease-
modifying therapies, which requires a better understanding of the mechanisms underlying AD. AD is
characterized by the spread of tau pathology through the brain in a stereotypical pattern that correlates well
with the disease progression. However, a critical need still exists to understand the molecular underpinnings of
tau toxicity in AD and thereby identify promising therapeutic targets to slow and/or halt AD progression. We
previously showed that tau aggregates disrupt anterograde fast axonal transport in the squid giant axon by
activating the protein phosphatase 1 (PP1)- glycogen synthase kinase 3β (GSK3β) signaling pathway which
causes the release of cargo from the anterograde motor protein kinesin through phosphorylation of kinesin light
chains by GSK3β. In tau aggregates, the exposure of an N-terminal epitope called the phosphatase activating
domain (PAD) activates this signaling pathway via interaction with and activation of PP1 in the squid giant
axon. Overactivity of this pathway results in aberrant cargo release and thus axonal transport deficits in the
squid. Furthermore, we recently demonstrated that interactions between the mutant P301L tau and PP1 results
in disrupted axonal transport in mammalian primary neurons, and the pathology is rescued upon PP1γ
knockdown. PAD exposure and axonal degeneration are evident early in the progression of AD and in other
tauopathies. Therefore, understanding the potentially toxic effects of PAD exposure is directly relevant to
disease. Mounting evidence suggests that tau pathology is propagated throughout the brain potentially in a
prion-like process involving cell-to-cell tau seeding. However, the functional consequences of seeded
aggregation of endogenous tau is not fully understood. The proposed experiments are designed to test the
hypothesis that AD brain-derived tau aggregates induce axonal degeneration in tau-seeded mammalian
neurons via activation of the PAD-PP1-GSK3β signaling pathway. The pathological consequences of seeding
with AD-derived tau pre-formed fibrils (PFF-tau) will be determined in functional live-cell axonal transport
assays. The activity of PP1 and GSK3β in PFF-tau-treated neurons will be measured using biochemical
assays. Furthermore, immunofluorescent staining, confocal microscopy and stereological measurement
techniques will be used to assess axonal and synaptic degeneration. Upon completion of this project, we will
have a better understanding of whether tau seeding in mammalian primary neurons causes toxicity through
activation of the PAD-PP1-GSK3β pathway. This new knowledge could inform the development of more
effective therapies for AD.

## Key facts

- **NIH application ID:** 10464286
- **Project number:** 1F31AG074521-01A1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Rebecca Lynn Mueller
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,942
- **Award type:** 1
- **Project period:** 2022-05-18 → 2023-11-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464286

## Citation

> US National Institutes of Health, RePORTER application 10464286, Investigating the functional consequences of seeding in mammalian primary neurons with Alzheimer’s Disease brain-derived tau filaments (1F31AG074521-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10464286. Licensed CC0.

---

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