understood.
Growing evidence suggests that early in AD brain blood flow is reduced and neurovascular coupling - which regulates the supply of oxygen and glucose to active brain regions - is dysfunctional. This neurovascular breakdown has been suggested to lead to neuronal death and cognitive deficits. While neurovascular coupling (NVC) dysfunction is widely cited as an early driver of AD-related cognitive decline, our recent findings challenge this dogma. We demonstrated that NVC remains largely preserved at key developmental stages in preclinical AD models. This suggests that the neurovascular breakdown observed in humans may be driven not by AD pathology alone, but by its synergy with peripheral vascular dysfunction.
This project will employ a novel dual-pathology model combining AD with atherosclerosis (ATH) to elucidate how peripheral vascular health modifies central neurovascular function. Typical techniques to be used in this project include: longitudinal optical imaging—including wide-field spectroscopy and high-resolution 2-photon microscopy to quantify cellular calcium dynamics and cerebral blood flow; behavioural assays of cognitive decline; and post-mortem immunohistochemistry to map the cellular architecture of the failing neurovascular unit. Throughout the project, the student will be trained in the advanced computational (e.g. MATLAB) and statistical skills necessary for data analysis.
This project will further our understanding of how, and when, neurovascular dysfunction contributes to AD progression and combine preclinical models of AD with a novel model of ATH to study how cardiovascular disease might affect AD progression.
References
Eyre B, Shaw K, Drew D, Rayson A, Shabir O, Lee L, Francis S, Berwick J, Howarth C. Characterizing vascular function in mouse models of Alzheimer's disease, atherosclerosis, and mixed Alzheimer's and atherosclerosis. Neurophotonics. 2025 Jan;12(Suppl 1):S14610. doi: 10.1117/1.NPh.12.S1.S14610. Epub 2025 May 21. PMID: 40405889; PMCID: PMC12094910.
Shabir O, Pendry B, Lee L, Eyre B, Sharp PS, Rebollar MA, Drew D, Howarth C, Heath PR, Wharton SB, Francis SE, Berwick J. Assessment of neurovascular coupling and cortical spreading depression in mixed mouse models of atherosclerosis and Alzheimer's disease. Elife. 2022 Jan 11;11:e68242. doi: 10.7554/eLife.68242. PMID: 35014950; PMCID: PMC8752088.
Sharp PS, Ameen-Ali KE, Boorman L, Harris S, Wharton S, Howarth C, Shabir O, Redgrave P, Berwick J. Neurovascular coupling preserved in a chronic mouse model of Alzheimer's disease: Methodology is critical. J Cereb Blood Flow Metab. 2020 Nov;40(11):2289-2303. doi: 10.1177/0271678X19890830. Epub 2019 Nov 23. PMID: 31760864; PMCID: PMC7585931.
