# Metabolic and neural activity normalization by cerebral blood flow increase in AD/ADRD models > **NIH NIH R01** · CORNELL UNIVERSITY · 2024 · $1,125,121 ## Abstract SUMMARY Although many biomarkers have been identified in AD/ADRD, the most important effect is cognitive function. Links between AD/ADRD symptoms and cerebral blood flow deficits or vascular risk factors such as hypertension are well recognized in patients, but the mechanisms are still under investigation. In mouse models of AD about 2% of capillaries are occluded by an arrested neutrophil and these stalled capillaries have a profound effect on cerebral blood flow. Such capillary stall perfusion deficits (CSPD) could reduce oxygenation and nutrient delivery to neurons and are therefore potential drivers of cognitive dysfunction in AD/ADRD. In AD mouse models, working memory performance is rescued within hours of reducing the incidence of stalled capillaries to increase cerebral blood flow using antibodies against the neutrophil protein Ly6G. CSPD has also been observed in a new non-amyloid ADRD model, hypertensive mice with targeted replacement of the murine ApoE gene with the AD-promoting ApoE4 human allele. In this mouse, rapid rescue of behavior and flow are observed after treatment with the platelet inhibitor prasugrel, suggesting a different cellular cause of CSPD than that observed in the AD models. The rapid time scales of cognitive recovery are too fast for many pathological processes and rule out vascular or neural remodeling. Instead, the speed of memory improvement suggests that changes in the dynamic firing pattern of neurons underlie the rescue and that improved metabolic support by increased cerebral blood flow is a critical factor in determining the functionality of neural circuits. This suggests that slower processes such as protein accumulation and remodeling can be secondary to fast effects linked to improvement of oxygen and metabolite delivery after blood flow increase. This proposal tests the idea that cerebral blood flow recovery leads to corrections in blood oxygenation and in oxygen usage, which then result in metabolic and cellular functional recovery in neurons (Aim 1). Such metabolic changes are hypothesized to underly corrections of aberrant neural activity that ultimately determine behavior. Aim 1 will use gamma oscillations, coordinated neural activity associated with healthy cortical function, as a simultaneous measure of the consequence of the oxygenation changes. In AD mouse models, an imbalance in the activity of inhibitory and excitatory neurons results in reduced fidelity of neural encoding of stimuli. Aim 2 asks if the blood flow improvement also corrects this activity imbalance and improves the precision of stimulus encoding for orientation tuned neurons in visual cortex. Aim 3 tests for normalization of activity in hippocampal circuits involved in the formation and consolidation of memory, directly testing the neural circuits involved in the memory tasks that CSPD reduction improves performance in. Age and sex dependence of these phenomena are investigated in the APP/PS1 model of AD and this study also compa... ## Key facts - **NIH application ID:** 10827964 - **Project number:** 5R01AG081931-02 - **Recipient organization:** CORNELL UNIVERSITY - **Principal Investigator:** CHRIS B SCHAFFER - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $1,125,121 - **Award type:** 5 - **Project period:** 2023-04-15 → 2028-01-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10827964 ## Citation > US National Institutes of Health, RePORTER application 10827964, Metabolic and neural activity normalization by cerebral blood flow increase in AD/ADRD models (5R01AG081931-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10827964. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*