Cognitive Restoration and Transcriptomic Reprogramming by AdipoRon After BCAS-induced Chronic Cerebral Hypoperfusion
Description: Vascular cognitive impairment and dementia (VCID) is a leading cause of cognitive decline and disability in older adults and arises primarily from chronic cerebral hypoperfusion. Sustained reductions in cerebral blood flow trigger persistent innate immune activation, white-matter degeneration, blood–brain barrier (BBB) dysfunction, and progressive cognitive impairment. Aging exacerbates these pathological processes, yet there are currently no disease-modifying therapies that directly target the neuroinflammatory and white-matter mechanisms underlying VCID. Adiponectin is an adipocyte-derived metabolic hormone with anti-inflammatory and neuroprotective actions in the central nervous system. Prior work supported by the American Heart Association demonstrated that pharmacological activation of adiponectin receptors using the orally bioavailable agonist AdipoRon improves cognitive outcomes, suppresses BBB disruption, and attenuates chronic neuroinflammation following reduced cerebral blood flow. Additional studies in traumatic brain injury models showed that AdipoRon preserves white-matter integrity and induces protective transcriptional programs in innate immune cells. However, whether adiponectin receptor activation is effective in an aged, clinically relevant VCID model and the immune mechanisms underlying its protective effects remain undefined. This project will extend these findings using an aged bilateral common carotid artery stenosis (BCAS) model that closely recapitulates human VCID. The central hypothesis is that adiponectin receptor activation preserves cognitive function after chronic cerebral hypoperfusion by suppressing maladaptive Microglia/Macrophage activation, mitigating white-matter injury, and inducing neuroprotective immune transcriptional programs. The specific aims are to determine whether AdipoRon improves cognitive outcomes and reduces neuroinflammation, white-matter injury, and neurovascular pathology after chronic hypoperfusion, and to define adiponectin-responsive immune gene networks using second-generation Visium-HD spatial single-cell RNA sequencing. This Bridge Career Development Award will generate essential functional and spatial transcriptomic data to support future NIH R01-level studies and aligns with the American Heart Association’s mission to address vascular causes of cognitive decline.
Funder: American Heart Association
Amount: $77,000
Funding type: fellowship
Funder scheme: Bridge Career Development Award
Start date: 2026-04-01
End date: 2027-03-31
Investigators: Hongjian Pu, Hongjian Pu
Institution: University of Pittsburgh
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Funded outputs count: 1
Funder award ID: 26BCDA1622663
OpenAlex ID: G3327201752