Assessment of Neurovascular Coupling &amp; Cortical Spreading Depression in Mixed Models of Atherosclerosis &amp; Alzheimer’s Disease

Shabir, Osman; Pendry, Ben; Lee, Llywelyn; Eyre, Beth; Sharp, Paul; Rebollar, Monica A; Howarth, Clare; Heath, Paul R.; Wharton, Stephen B.; Francis, Sheila E.; Berwick, Jason

doi:10.1101/2020.08.13.249987

Cited by 1 publication

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“…The other studies utilised an acute preparation in which the mouse underwent cranial window surgery and was still anaesthetised when neuronal or haemodynamic recordings were undertaken. As mouse models of disease can be more susceptible to cortical spreading depression after invasive surgery (Shabir et al, 2020), and APOE4 is associated with an enhanced inflammatory phenotype (Kloske and Wilcock, 2020), the increased pathology observed in acute preparations may be due to this increased sensitivity to surgery and/or anaesthesia. Our findings, that there is an enhancement of neuronal activity and a slight disruption of vascular function, are a much closer approximation to the mild changes seen in young to middle-aged human APOE4 carriers (Henson et al, 2020; O’Donoghue et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

APOE4 expression confers a mild, persistent reduction in neurovascular function in the visual cortex and hippocampus of awake mice

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et al. 2021

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Vascular dysfunction is an early feature of late onset Alzheimer's disease (AD), preceding classic AD pathology such as beta amyloid accumulation and formation of hyperphosphorylated tau. Such vascular dysfunction may promote classic AD pathology by decreasing blood flow, impairing brain oxygenation and clearance of molecules such as beta amyloid. The main genetic risk factor for AD is the ϵ4 allele of APOE, which has been found to increase blood brain barrier permeability and decrease vascular density, as well as decrease blood flow and functional hyperaemia in anaesthetised mice undergoing acute surgery. These results suggest that APOE4 may confer AD risk via its effects on the vasculature. However, the responses of neurons and individual vessels have not been studied, so neurovascular relationships are unknown, and no previous studies have looked at awake mice. We therefore measured neurovascular responses at rest and in response to visual stimulation using 2 photon imaging of awake APOE3 and APOE4 targeted-replacement (APOE TR) mice that expressed the calcium indicator GCaMP6f in excitatory neurons, while labelling the vascular lumen with Texas Red dextran. In parallel, we measured cerebral blood flow, blood oxygenation and cerebral blood volume using combined laser Doppler flowmetry and haemoglobin spectrometry. Measurements were performed in mice aged between 3-4 months to 12-13 months. We found a milder vascular deficit in awake mice than previous studies that used an acute surgical preparation: capillary responses to visual stimulation were the same in APOE3 and APOE4 TR mice, leading to unimpaired functional hyperaemia. However, neuronal calcium signals during visual stimulation were significantly enhanced in APOE4 mice, while there was a marked decrease in pial arteriole responsiveness and vasomotion. This pattern of results was unaffected by age, suggesting that APOE4 expression creates a stable, but mildly altered neurovascular state that does not itself cause degeneration. However, these changes likely make the system more sensitive to subsequent insults; for example, weaker vasomotion could impair clearance of beta amyloid as it starts to accumulate, and therefore may help explain how APOE4 expression increases risk of developing AD.

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