# Identifying Determinants of Tau Pathology Seeding

> **NIH NIH F31** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $47,974

## Abstract

PROJECT SUMMARY/ABSTRACT
 Alzheimer's disease (AD) is the most common neurodegenerative disorder in the United States and is
projected to affect 14 million people by 2060. Accumulation of tau pathology in AD strongly correlates to
patients' cognitive decline. Current models of progressive tau pathology rely on either transgenic mice or tau
fibrils isolated from the diseased human brain in wild-type mice. Attempts to induce tau pathology in wild-type
mice using recombinant tau fibrils have failed. Recent studies have revealed structural and post-translational
differences between recombinant and human-derived tau fibrils that may drive this difference in seeding
capacity.
 The overarching goal of this fellowship is to use in vitro and in vivo methods to determine the
conformational and environmental drivers of tau pathology seeding. Recent work produced truncated tau fibrils
with various core structures, including one with a core that is structurally identical to the core region of AD
PHFs. Yet, these recombinant fibrils lack post-translational modifications associated with neurofibrillary
tangles. Proteomic work has identified post-translationally modified residues on the tau protein associated with
pathology, and many of these disease-associated post-translational modifications can be introduced by
producing tau in insect cells. The proposed research will take advantage of these recent innovations to assess
the role of tau fibril structure and post-translational modifications in seeding capacity. Aim 1 of this work will
use tau fibrils with varying core structures, including those identical to AD tau, and post-translational
modifications to evaluate the pathological seeding capacity in a primary neuron culture model. Aim 2 of this
work will utilize a quantitative pathology modeling workflow to quantify progressive pathological seeding of
selected tau fibrils in wild-type mice over the course of nine months. The data collected and training acquired
during this fellowship not only have the potential to shape future model systems in AD but will also shape and
focus my trajectory towards becoming a leader in neurodegenerative research.
 Under this training period at Van Andel Research Institute, I will develop technical skills in image
analysis, mouse neuroanatomy, and negative stain EM. I will also have ample opportunity to gain confidence in
both oral and poster presentations. My collaborations with the cryo-electron microscopy core at VAI, a
biotechnology company, and a world leader in tau fibril structure will allow me to gain expertise in running
collaborative projects in addition to receiving additional guidance on structure-based questions in the field of
neurodegenerative disease.

## Key facts

- **NIH application ID:** 10903314
- **Project number:** 1F31AG084199-01A1
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Alysa Marie Kasen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $47,974
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903314

## Citation

> US National Institutes of Health, RePORTER application 10903314, Identifying Determinants of Tau Pathology Seeding (1F31AG084199-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10903314. Licensed CC0.

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