Age-related impairment of cerebral blood flow response to K_ATP channel opener in Alzheimer’s disease mice with presenilin-1 mutation

Abstract

Local cerebral blood flow (CBF) responses to neuronal activity are essential for cognition and impaired CBF responses occur in Alzheimer’s disease (AD). In this study, regional CBF (rCBF) responses to the KATP channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1M146V) mice from three age groups using Laser-Doppler flowmetry. The rCBF response was reduced early in young 3xTgAD mice and almost absent in old 3xTgAD mice, up to 30%–40% reduction with altered CBF velocity and mean arterial pressure versus WT mice. The impaired rCBF response in 3xTgAD mice was associated with progression of AD pathology, characterized by deposition of intracellular and vascular amyloid-β (Aβ) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine abolished rCBF response to diazoxide suggesting NO was involved in the mediation of vasorelaxation. Levels of phosphor-eNOS (Ser1177) diminished in 3xTgAD brains with age, while the rCBF response to the NO donor sodium nitroprusside remained. In PS1M146V mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1M146V contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aβ oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1M146V mutation.

Impaired dynamics of brain precapillary sphincters and pericytes at first order capillaries explains reduced neurovascular functions in aging

“…A preserved brain vascular supply is required to ensure the delivery of enough glucose and oxygen to support information processing and cognition. In neurodegenerative diseases, the aging-related impairment of K ATP channels and NO-signaling pathways, neurovascular uncoupling, and pericyte process rarefaction and decrease in capillary density are further exacerbated (38–40). In this study, we report preserved neuronal activity in aged brains upon WP stimulation ( Fig.…”

“…In patients, isocapnic hypoxia opens K ATP channels and causes an increase in the CBF, thereby maintaining oxygen delivery and brain partial O 2 (46). With age, the increase in CBF produced by K ATP channel opening is reduced, and this is further aggravated at an early stage of AD and likely caused by reduced expression of K ATP channels (38). Long-term treatment of AD mice at an early stage with K ATP channel opener improves cognitive function and reduces the tau and amyloid burden (47).…”

APOE genotype moderates the relationship between LRP1 polymorphism and cognition across the Alzheimer's disease spectrum via disturbing default mode network

“…Thirdly, LRP1 mediated vascular clearance of Aβ from the brain 49 ; hence, abnormal vascular function might induce cerebral hemodynamic dysregulation and further aggregate Aβ deposition. Previous studies have reported that microvascular lesions altered Aβ plaques 50 ; local cerebral blood flow responses to neuronal activity were impaired in AD 51 ; and neurovascular dysregulation even occurred in middle‐aged APOE ‐ε4 carriers. 52 Nevertheless, aerobic exercise significantly improved hippocampal blood flow in hypertensive APOE ‐ε4 carriers, which might be beneficial for individuals at high risk of AD.…”

Nicorandil attenuates cognitive impairment after traumatic brain injury via inhibiting oxidative stress and inflammation: Involvement of BDNF and NGF

“…Intriguingly, current investigations suggest that activation of the KATP channel significantly contributes to cerebrovasodilation and plays a pivotal role in autoregulation both of which are impaired in the context of TBI (Pastor et al, 2019). Furthermore, emerging evidence confirms that blockage of KATP channel is closely associated with cognitive impairment (Liu et al, 2021;Moriguchi et al, 2021). These findings raise questions that nicorandil may represent a promising approach for ameliorating cognitive impairment after TBI.…”