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Tau acetylated PHF6 and APOE reactive T cells presented by HLA-DRB1*04:04 in Alzheimer'sDisease

Award Number: R03AG095471
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Tau acetylated PHF6 and APOE reactive T cells presented by HLA-DRB1*04:04 in Alzheimer'sDisease - Abstract: Alzheimer’s disease (AD) is the most common cause (60-80%) of dementia with multifaceted neuropathological features. It has become clear in the past two decades that the adaptive immune system, of which T cells and human leukocyte antigens (HLAs) are two major parts, does act in the brain. However, little is known about the fragments (peptides) that those T cells react to and the phenotypes of those T cells in AD. The T cell receptors (TCRs) on the surface of T cells recognize and bind to peptides. Because of the enormous diversity of TCR repertoire, there is a need for high-throughput identifying functional TCRs which is underdeveloped. One hallmark of AD is neurofibrillary tangles (NFTs) in patients’ brains. NFTs are formed by self-aggregation of the microtube-associated protein, namely tau. A specific piece of tau consisting of six amino acids, paired helical filament (PHF)6 (VQIVYK), plays a predominant role in tau self-aggregation. Another protein, apolipoprotein E (APOE) is the most significant genetic risk factor in AD and there are three different common forms of APOE: ε2, ε3 and ε4. Their differences are amino acids at position 112 and 158. The ε4 has arginines (Arg112/Arg158) and ε2 has cysteines (Cys112/Cys158) at both sites, while ε3 has cysteine at position 112 and arginine at 158 (Cys112/Arg158). The ε4 increases the risk for AD relative to ε3 while ε2 is protective against the disease. The adaptive immune system is now considered a major part and plays an important role in AD. An adaptive immune response is initiated when TCRs on the surface of T cells recognize a small piece of antigens (9-15 amino acids), which are presented by HLA; this immune response can be either protective or detrimental. A particular HLA-DRB1*04:04 has the strongest protective effect. We hypothesize that an immune response mediated by HLA-DRB1*04:04 targeting APOE ε2 and tau PHF6, particularly with the lysine at 311 (K311) modified by acetylation (namely PHF6 aK311), has a protective effect to the disease. Aim1 of this project will detect, isolate, and characterize T cells targeting tau PHF6 aK311 and APOE presented by DRB1*04:04 using advanced immunological techniques, including tetramer HLA staining at both culture and baseline, plate- based single-cell RNA sequencing using SMART-Seq® technique with ultimate sensitivity and mimicking adaptive immune signaling in TCR transfected cells. Further, Aim 2 will develop a high-throughput method using DNA blocks to screen and identify ~10,000 TCRs in one experiment, and TCR libraries generated in this project can be simply and effectively reused, shared, expanded, and applied to other antigens and HLAs associated with other human disorders. This project is significant not only for investigating tau and APOE reactive T cells but also for the protective role of this immune response in AD, which helps clear abnormal tau and slow down AD progression, leading to potential therapeutical development like peptide vaccination and chimeric antigen receptor (CAR)-T cells. Another significance of this project is that high-throughput identifying functional TCRs in three immune signal pathways is a powerful tool to find a large number of activated specific TCR clonotypes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $311,600 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	1	9/14/2026	NEW	$311,600
														Subtotal = $311,600

Grand Total All Awards = $311,600

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Tau acetylated PHF6 and APOE reactive T cells presented by HLA-DRB1*04:04 in Alzheimer'sDisease

Award Number: R03AG095471

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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