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Investigating the contributions and impact of neutrophil activity in a comorbid model of AD and VCID

Award Number: F32NS141892
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/16/2025
PERIOD OF PERFORMANCE END DATE: 05/15/2027

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Investigating the contributions and impact of neutrophil activity in a comorbid model of AD and VCID - Project Summary/Abstract Alzheimer’s disease (AD) is the most common form of dementia often presenting with vascular contributions to cognitive impairment and dementia (VCID). Growing evidence has highlighted pathological contributions from an immune cell within the peripheral immune system: neutrophils. In cases of hyperhomocysteinemia (HHcy), a common risk factor for VCID, neutrophils cause vascular damage by oxidative stress and releasing products for matrix degradation as well as increasing blood hypercoagulability via release of neutrophil extracellular traps (NETs), any of which can be a confounding factor in current therapeutics. This proposal aims to investigate the mechanisms by which neutrophils are contributing to worsened cerebrovascular outcomes in AD and VCID, and the impact of depleting neutrophils on disease pathology to give a broader picture of immune-mediated neuropathologies. To answer these questions, we propose to examine the neutrophil response to APP, VCID, and APP-VCID comorbidities (Aim 1) and determine whether chronic depletion of neutrophils reduces neuropathology for each case (Aim 2). We hypothesize that mechanisms unique to each pathology will be additive while overlapping mechanisms across pathologies will be exacerbated. For Aim 1, cohorts of wild-type or Tg2576 mice will be placed on control diet or diet to induce HHcy. In vivo multiphoton microscopy imaging, flow cytometry, single- cell RNA sequencing, and intravascular labeling of leukocytes prior to tissue collection will be used to examine upregulated mechanisms. In Aim 2, mice from Aim 1 will be given isotype control antibody or murinized anti- Ly6G antibody for chronic neutrophil depletion at the start of diet to assess changes in physiological and cognitive outcomes. We will test the hypothesis that chronic depletion reduces the severity of comorbid disease pathology by longitudinal imaging using MRI, multiphoton imaging, and immunohistochemical assays for neuroinflammation and vascular damage. These aims will provide important information on an overlooked factor to vascular dementias. Achievement of these aims will aid in my own goals of becoming an independent researcher by improving my scientific knowledge of VCID and AD as well as supplement my available research skills in MRI, immunohistochemistry, and single-cell transcriptomics. To complete these aims, I have the resources at Indiana University – Indianapolis such as the Alzheimer’s Disease Research Center as part of the NIH, a program for developing new mouse models (MODEL-AD) to be used for investigating new treatments (TREAT- AD), as well as a well-equipped environment for dementia-related studies. My mentor, Dr. Wilcock, and mentoring committee will guide my professional development by providing assistance with my written and communicative skillsets as well as expanding upon my academic network. Overall, this proposal will provide both scientific and professional development training while adding important knowledge to the AD/VCID field.


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 = $75,880 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/11/2026	NON-COMPETING CONTINUATION	$75,880
														Subtotal = $75,880

Issue Date FY: 2025 ( Subtotal = $74,632 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/16/2025	NEW	$74,632
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	6/16/2025	NEW	$0
														Subtotal = $74,632

Grand Total All Awards = $150,512

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Investigating the contributions and impact of neutrophil activity in a comorbid model of AD and VCID

Award Number: F32NS141892

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/16/2025

PERIOD OF PERFORMANCE END DATE: 05/15/2027

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