Targeting Inflammation-Resolution Pathways to Limit VCID

There are currently no effective therapies to reduce vascular contributions to cognitive impairment and dementia (VCID), which contribute to the overall burden of Alzheimer’s Disease and Related Dementias (ADRDs). This gap necessitates exploration of new cellular programs and mechanisms associated with VCID. Dementia risk is increased by 2.5 fold in patients with atherosclerosis. Thus, atherosclerosis is a major contributor to ADRDs yet therapies that target ADRDs in this context is a major gap. Cholesterol lowering, which is the primary treatment for atherosclerosis, is not sufficient to curtail ADRDs, and we posit that non-traditional risk factors linking both atherosclerosis and VCID may reveal new therapeutic strategies to limit ADRDs. Non-resolving inflammation is an underpinning for both atherosclerosis and VCID. The resolution of inflammation is regulated in part by the balance between specialized pro-resolving mediators (SPMs), like resolvins (e.g Resolvin D2, RvD2) and pro- inflammatory mediators like leukotrienes and some of prostanoids. SPMs restrain excessive neutrophils (PMN) migration into tissues and activate pro-reparative monocytes/macrophages (M), whereas PGs derange brain M function which is associated with cognitive aging. Yet, major gaps exist in our understanding of: (a) mechanisms associated with impaired resolution in VCID and (b) how SPMs could promote resolution in VCID. Thus, the overall objective of this R01 is to investigate mechanisms of defective resolution in VCID and to harness SPM signaling pathways towards a novel treatment strategy. Our central hypothesis is that elevated and sustained myeloid cells promote VCID in atherosclerosis, and that treatment with SPMs limits myeloid cells and VCID in middle age. Proof-of-concept VCID models exclude pathophysiologial roles of atherosclerosis, and our proposal offers this key translational focus. Thus, we aim to a) uncover cell type(s) and mediators that drive non-resolving inflammation (Aim 1), b) determine causation for endogenous resolution signaling (Aim 2) and c) test SPMs as a therapy (Aim 3) in VCID. These Aims address a fundamental gap in our understanding of the physiologically relevant context of middle-age in VCID. Completion of the proposed studies will provide mechanistic insight into dysregulated resolution processes in middle-age, define cells, mediators and mechanisms that exacerbate VCID and establish rationales for novel therapies to reduce the burden of dementia. Project Number: 1RF1NS140762-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Gabrielle Fredman (+1 co-PI) | Institution: ALBANY MEDICAL COLLEGE, ALBANY, NY | Award Amount: $1,951,689 | Activity Code: RF1 | Study Section: Special Emphasis Panel[ZRG1 AN-W (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366580