One of the earliest biomarker abnormalities in Alzheimer’s Disease is a reduction in cerebral blood flow (CBF). Blood flow to the brain is regulated by the intrinsic properties of arteries to constrict and relax in response to different stimuli, such as intraluminal pressure. Our recent work  (Taylor et al., 2022 – PMID: 37549299) has shown that Ca2+ release events from the sarcoplasmic reticulum (SR) and subsequent large-conductance Ca2+-activated K+ (BK) channel activation are disrupted in 18-month male APP23 mice compared to wild-type (Wt) controls. BK channels promote a more hyperpolarised smooth muscle that prevent excessive vasoconstriction in response to increases in intraluminal pressure. Therefore, a reduced BK channel activity results in a more contractile artery that contributes to reduced CBF. We also showed that acute exposure to Aβ(1-40) disrupts intracellular vascular smooth muscle cell (VSMC) Ca2+ signalling in healthy cerebral arteries, characterised as an increase in pathogenic Ca2+ waves. This project looked to determine if there was a reduction in CBF in male and female APP23 mice, at 9 months of age, to determine if this age represented an intermediate phenotype between 18 month APP23 mice and acute Aβ(1-40) exposure. 

All experiments were covered by the UK Home Office Guidance on the Operation of the Animals (Scientific Procedures) Act 1986 and approved by a local committee (PPL: PP9466981). 9-month APP23 mice display reduced CBF compared to Wt littermates (1082 ± 24.3 vs. 999 ± 25.03, p < 0.0001, n = 10 each group) shown by laser speckle imaging. Spontaneous transient outward currents (STOCs) were recorded to measure BK channel activity on freshly isolated pail artery SMCs over a range of membrane potentials. Pial artery SMCs isolated from APP23 mice showed a decreased STOC frequency (p < 0.05, n = 15 each group) and amplitude (p < 0.05, n = 15 each group) compared to cells isolated from Wt littermates. Ex-vivo pressurised pial arteries from APP23 mice showed dysregulated Ca2+ signalling. APP23 arteries loaded with the Ca2+ indicator (Cal-520) showed a decreased Ca2+ spark frequency (15.72 ± 2.736 vs. 9.872 ± 1.192 Hz,  p < 0.05, n = 18 each group) and an increased Ca2+ wave frequency (0.02582 ± 0.004478 vs. 0.07144 ± 0.009742 waves/cell/s, p < 0.0001) compared to Wt littermates. To determine SR store load, a caffeine bolus was applied to APP23 arteries and showed a ~40% reduction in the Ca2+ transient (3.025 ± 0.5442 vs. 1.70 0± 0.2785 AUC, p < 0.05, n = 18 each group) compared to Wt littermates. 

9-month APP23 mice have reduced Ca2+ in the intracellular store, that disrupts correct Ca2+ signalling. This reduces BK channel activity and contributes to a more contractile artery and reduced CBF. Future experiments will determine the mechanisms reducing store load and if this can be restored following treatment.