Author: Kang Lai, Class of 2026

Functional hyperemia, or the dilation of blood vessels in response to increased metabolic activity, is critical for regulating the levels of oxygen and glucose in the brain. Moreover, it facilitates the clearance of metabolic byproducts such as amyloid-β peptide (Aβ), an accumulation of which underlies Alzheimer’s disease. In Alzheimer’s Disease (AD), disruptions in vascular dynamics are significant but poorly understood contributing features of pathology. 

Dr. Shaoyu Ge and colleagues in the Department of Neurobiology at Stony Brook University investigated the effects of hippocampal interneuron activity on functional hyperemia before and after Aβ accumulation. His team uses in vivo electrophysiology recordings to measure excitatory and inhibitory neuronal firing, in vivo optical imaging, and chemogenetic tests. Researchers analyzed prior to AD using wild type (WT) mice and after the onset of AD using two mice models: App^SAA Knock-in (AppKI mice) and J20 mice, both of which express amyloid precursor protein (APP) mutations.

Using in vivo optical imaging, the team measured the contrast of optical signals between red blood cells and plasma to obtain blood flow velocity and direction of flow. In an enriched environment (EE), AppKI mice showed prolonged functional hyperemia in the hippocampus prior to Aβ accumulation, unlike WT and J20 mice. Within aging and Aβ accumulation, the hyperemia declined rapidly in APPKI mice and J20 mice indicating vascular dysfunction with aging. In addition, EE has been found to activate hippocampal inhibitory neurons. Activation of these neurons chemogenetically through Designer Receptors Exculisively Activated by Designer Drugs (DREADDS) has increased nitric oxide (NO) signaling and production, causing increased blood flow velocity. Notably, interneuron–but not excitatory dentate granule cell–activity remained elevated in AppKI mice compared to wild type (WT) mice, explaining the prolonged functional hyperemia. Finally, Dr. Ge tested whether hyperemia itself drives pathology. Through immunostaining and L-NAME, a treatment used to inhibit hyperemia, and suppress NO signaling in AppKI mice suggests a decrease in hippocampal Aβ accumulation in 4-and 6-month-old AppKI mice, suggesting excessive hyperemia as a contributing cause of Aβ deposition. 

These findings reveal a critical role for early neurovascular dysfunction in AD  progression, and suggest that targeting neurovascular coupling as a therapeutic potential in early AD. Future studies include the examination of astrocytes, microglia, and interneuron subtypes to fully understand interactions between vascular and neuronal dynamics in Alzheimer’s disease. 

Figure 1. https://pmc.ncbi.nlm.nih.gov/articles/PMC11750623/

Work’s Cited

[1] Kim, T. A., Cruz, G., Syty, M. D., Wang, F., Wang, X., Duan, A., Halterman, M., Xiong, Q., Palop, J. J., & Ge, S. (2025). Neural circuit mechanisms underlying aberrantly prolonged functional hyperemia in young Alzheimer’s disease mice. Molecular psychiatry, 30(2), 367–378. https://doi.org/10.1038/s41380-024-02680-9

[2] Image from https://unsplash.com/photos/a-white-brain-on-a-black-background-aKMcboPYZZw