By Asher Agarwal, Class of 2027

When a region of our brain is active, blood vessels dilate to increase blood flow and meet the increased metabolic demand of the area. This is known as functional hyperemia, or neurovascular coupling, and it is critical for maintaining metabolic homeostasis in the brain. Previous research has shown that, in response to novel environments, hippocampal inhibitory interneurons are stimulated and release nitric oxide (NO), causing vasodilation, which increases blood flow. Neurovascular dysfunction has been recognized as a common symptom associated with Alzheimer’s disease (AD). However, the time of its onset relative to the amyloid-beta (Aβ) accumulation, the overproduction of which is a hallmark of AD, had not yet been studied. Complications with the amyloid peptide precursor (APP) gene are a cause of Aβ accumulation, which causes AD pathology. Researchers from the Ge Lab set out to find out when and how neurovascular dysfunction occurs and possibly contributes to pathogenesis in the early stages of Alzheimer’s disease, prior to Aβ plaques. 

Researchers used AppKI and J20 AD mouse models, which overexpress human APP genes via knock-in, to compare functional hyperemia and the neural circuits underlying that mechanism. In vivo (inside the body) optical imaging was used to analyze blood flow dynamics in the AD mouse models and in vivo electrophysiology was used to record the activity of hippocampus interneurons. Optical imaging for blood flow revealed abnormally prolonged functional hyperemia in mice in response to novel context exploration, prior to Aβ accumulation. In addition, electrophysiology recordings revealed increased activation of hippocampal interneurons before Aβ accumulation. To prove these results could be caused by hippocampal inhibitory interneurons alone and not by outside factors, the researchers chemogenetically activated them. Their activation was proven to induce hyperemia before Aβ accumulation in AD mice. Then, after Aβ accumulation, blood flow rapidly decreased.

The findings of this study reveal a significant mechanism of AD pathology: prolonged functional hyperemia prior to Aβ plaque formation. Researchers then also inhibited neurovascular coupling by suppressing NO, which was found to decrease Aβ accumulation. These results suggest that targeting early neurovascular dysfunction is a potential therapeutic approach for treating AD. Intervention at this stage would be critical to the development of AD treatment because once Aβ plaques form, there is almost no reversing the disease progress. Early intervention can therefore prolong patients’ cognitive health beyond what was previously possible.

Figure 1 A doctor examining MRI imaging of a brain.

Works Cited: 

[1] T. Kim, et al., Neural circuit mechanisms underlying aberrantly prolonged functional hyperemia in young Alzheimer’s disease mice. Molecular Psychiatry (2024). doi: 10.1038/s41380-024-02680-9.

[2] Image retrieved from: https://www.pexels.com/photo/a-doctor-holding-an-mri-result-of-the-brain-4226219/