Friday, October 31, 2025 10/31/2025

CNS Exosomes-Mediated Adaptive Immunity in Alzheimer's Disease (AD)

Award Number: R01AG078728
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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CNS Exosomes-Mediated Adaptive Immunity in Alzheimer's Disease (AD) - Abstract Alzheimer’s disease (AD) remains one of the most unmet medical challenges in our society. In the AD, neuroinflammation has been increasingly recognized to play a central role in the pathogenesis of AD, in addition to extracellular amyloid plaques and hyperphosphorylated tau based neurofibrillary tangles. Although the role of innate immunity especially represented by microglia is well-established in AD, it is far less understood and established about whether and how the T or B cell-mediated adaptive immunity is involved in AD pathogenesis. In particular, whether there are brain- and AD-specific antigens to activate adaptive immunity and how these antigens travel to peripheral remain to be investigated. Exosomes (size 40-100 nm), a major type of secreted extracellular vesicles (EVs), are derived from intraluminal vesicles (ILV) that are budded inwardly from the early endosomal compartment and are released from multiple vesicular bodies (MVB) during the maturation of endosomes. EVs and exosomes secreted from various CNS cell types have emerged as a novel and important intercellular pathway in the. Exosome-mediated secretion has also been implicated in initiation and propagation in AD. Although exosomes secreted from various peripheral cell types especially immune and tumor cells trigger immune responses, whether and how CNS-derived exosomes are immunogenic remains unexplored. By employing cell-type specific ILV/exosome reporter (hCD63-GFPf/f) mice we recently generated, we showed that astroglia-derived exosomes are associated with Aquaporin 4+ (Aqp4+) perivascular end feet/blood vessel in the brain. hCD63-GFP+ astroglial exosomes can also be detected in blood serum of LPS-injected (but not control) Glast-CreER+CD63-GFPf/+ mice. Excitingly, exosomes secreted from “reactive” astroglia (RAEs) strongly activate CD4+ and CD8+ T cells in vitro and in vivo. Based on previous studies and our preliminary results, we propose to investigate the following aims: 1) Determine pathological efflux of CNS cell-type specific exosomes from brain and their entry into peripheral circulation in AD models; 2) Determine antigenicity of AD- relevant astroglial exosomes in activating T cells in vitro and in vivo. We have generated a large amount of preliminary data to support our rationales and to demonstrate feasibility for proposed aims. We will employ mouse genetics, virus injections, immunohistochemical (IHC) analysis and in vivo two-photon imaging, primary cultures, FACS, and biochemical approaches to investigate these two aims. Results from this project will determine the efflux changes of neuron or astroglial exosomes from the brain and these exosomes’ entry into peripheral circulation in AD models. In addition, our current study will investigate how T cells respond to “reactive” astroglial exosomes. As reactive astroglia is commonly observed in neurodegenerative diseases including AD, this will potentially unveil new mechanisms how T cells are involved in AD pathogenesis and help define specific brain signals to activate T cells in AD, which subsequently facilitate the therapeutic development.


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: 2025 ( Subtotal = $816,608 )
2025	2025	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	4	7/28/2025	NON-COMPETING CONTINUATION	$816,608
														Subtotal = $816,608

Issue Date FY: 2024 ( Subtotal = $896,099 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	3	6/4/2024	NON-COMPETING CONTINUATION	$896,099
														Subtotal = $896,099

Issue Date FY: 2023 ( Subtotal = $898,610 )
2023	2023	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	2	5/24/2023	NON-COMPETING CONTINUATION	$898,610
														Subtotal = $898,610

Issue Date FY: 2022 ( Subtotal = $933,576 )
2022	2022	TRUSTEES OF TUFTS COLLEGE	136 HARRISON AVE	BOSTON	MA	02111	SUFFOLK	USA	Aging Research	000	1	8/17/2022	NEW	$933,576
														Subtotal = $933,576

Grand Total All Awards = $3,544,893

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CNS Exosomes-Mediated Adaptive Immunity in Alzheimer's Disease (AD)

Award Number: R01AG078728

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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