# A novel blood-CSF adaptive immune response in Alzheimer's disease

> **NIH NIH R00** · NORTHWESTERN UNIVERSITY · 2024 · $241,531

## Abstract

Project Summary/Abstract
Alzheimer’s disease (AD) is an incurable neurodegenerative disorder in which neuroinflammation is increasingly
recognized to play a critical function. While innate inflammation has been implicated in AD, little is known about
the contribution of the adaptive immune response. Preliminary data featured in this application demonstrate a
peripheral immune signature of AD characterized by increased numbers of highly-differentiated CD8+ T effector
memory CD45RA+ (TEMRA) cells. Strikingly, CD8+ TEMRA cells were also present in patient cerebrospinal fluid
(CSF) and T cell receptor (TCR) sequencing indicated their clonal expansion, suggesting antigen specificity of
these adaptive immune cells. TCR cloning and peptide screens demonstrated specificity of a subset of clonally
expanded AD CSF TCRs to the Epstein-Barr virus (EBV) BZLF1 antigen. These results provide the first evidence
of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related
neurodegeneration. This K99/R00 application will test the novel theory of a detrimental adaptive immune
response contributing to AD pathobiology. In Specific Aim 1, AD blood-CSF T cell clonotypes will be related to
CSF biomarkers. This approach will determine specific T cell populations in AD and whether these cells relate
to disease severity. In Specific Aim 2, antigen identification screens will be used to detect the self/non-self
antigen(s) driving T cell clonal expansion in AD. These assays could uncover a novel therapeutic target or
biomarker for AD. Specific Aim 3 will determine mechanisms of T cell-mediated neuronal death and resiliency
in AD using induced neuronal (iN) cells co-cultured with patient CSF CD8+ T cells. These experiments will assess
whether AD CSF CD8+ T cells mount cytotoxic effector responses to iN cells infected with EBV and/or to a
molecular mimic of BZLF1. The candidate, Dr. David Gate, has extensive experience in T cell biology and has
spent more than a decade studying AD. During the mentoring phase of this award, Dr. Gate aims to advance his
knowledge in next-generation sequencing analysis, sophisticated statistical methods, antigen screening, iN
culturing methods and CRISPR gene editing. Dr. Gate's mentor and co-mentor, Dr. Tony Wyss-Coray and Dr.
Mark Davis, respectively, have comprehensive expertise in these areas. They will provide an enriching
environment for Dr. Gate to develop as a prominent independent investigator in neuroimmunology research. As
an independent investigator, Dr. Gate will leverage the training under this fellowship to comprehensively and
quantitatively evaluate the interactions between T cell molecular components and neurodegeneration.

## Key facts

- **NIH application ID:** 10757339
- **Project number:** 5R00NS112458-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** David Gate
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $241,531
- **Award type:** 5
- **Project period:** 2020-07-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757339

## Citation

> US National Institutes of Health, RePORTER application 10757339, A novel blood-CSF adaptive immune response in Alzheimer's disease (5R00NS112458-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10757339. Licensed CC0.

---

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