Biology subjects

Stackhouse, T. L.

Publications and source records attributed to Stackhouse, T. L..

3 recordsLinked to original sources

bioRxiv2026

Stroke and Alzheimer's disease have distinct consequences on neurovascular function but synergize to increase amyloid deposition

INTRODUCTION: We examined whether stroke induces chronic cerebrovascular dysfunction and thereby exacerbates A{beta} pathology. METHODS: We exposed Tg2576 mice to a transient mild subcortical ischemia and examined cerebrovascular function at chronic timepoints as well as reactive astrocytes and A{beta} deposition post-mortem. RESULTS: Baseline cerebral blood flow and cerebrovascular reactivity (CVR) are both influenced by anesthesia regimen. A{beta} strongly impairs CVR at earlier ages, while mild ischemia impairs CVR at later ages. Mild ischemia reduces neurovascular coupling more strongly than A{beta} and synergistically increases A{beta} deposition in Tg2576 mice. DISCUSSION: Stroke-induced cerebrovascular dysfunction and astrocyte reactivity persist for long periods after the injury. Although there is variability in the spatiotemporal progression of ischemia- and A{beta}-induced vascular impairments, they generally follow the pattern of Thal staging. Surprisingly, the ischemia+A{beta} group showed the least cerebrovascular dysfunction yet an exacerbation of A{beta} deposition, suggesting that these pathologies are connected but not tightly coupled.

neuroscience↗

bioRxiv2025

Mild subcortical stroke induces widespread astrogliosis independent of microglia and age

Ischemic stroke induces a plethora of pathophysiological changes, including neuroinflammation and chronic cerebrovascular dysfunction. In humans, even small, silent strokes can trigger these pathologies, which can spread to brain regions far beyond the infarct and persist chronically, ultimately worsening prognosis and increasing the risk for vascular dementia and Alzheimers disease. The cause of this extensive pathology is unknown, but reactive astrocytes and microglia are likely contributors. Here, we describe an optimized short-duration middle cerebral artery occlusion model that produces a clinically relevant small stroke confined to subcortical regions, similar to most silent strokes in humans. We termed this model the mild subcortical infarct (MSCI). We then mapped the spatiotemporal extent of reactive astrocytes and microglia during the sub-acute period (1, 3, and 7 days) following MSCI. We observed that reactive astrogliosis develops more rapidly and spreads more extensively, permeating the entire middle cerebral artery territory, compared to the reactive microglial response following this small infarct. Microglial depletion resulted in larger infarct sizes but did not prevent the reactive astrocytes, suggesting that ischemia-driven astrogliosis is largely microglia-independent. Lastly, we show that aging mice exposed to MSCI exhibit a comparably strong response of reactive astrocytes and microglia as young mice. We propose that MSCI is a novel and valuable model for examining the subtle yet highly important chronic effects of stroke. It may be especially useful for investigating the influence of reactive astrogliosis on pathologies like neuroinflammation and cerebrovascular dysfunction in regions distal from the primary injury site.

neuroscience↗

bioRxiv2021

Increased 20-HETE signaling suppresses neurovascular coupling after ischemic stroke in regions beyond the infarct

Neurovascular coupling, the process by which neuronal activity elicits increases in the local blood supply, is impaired in stroke patients in brain regions outside the infarct. Such impairment may contribute to neurological deterioration over time, but its mechanism is unknown. Using the middle cerebral artery occlusion (MCAO) model of stroke, we show that neuronal activity-evoked capillary dilation is reduced by [~]75% in the intact cortical tissue outside the infarct border. This decrease in capillary responsiveness was not explained by a decrease in local neuronal activity or a loss of vascular contractility. Inhibiting synthesis of the vasoconstrictive molecule 20-HETE, either by inhibiting its synthetic enzyme CYP450 {omega}-hydroxylases or by increasing nitric oxide (NO), which is a natural inhibitor of {omega}-hydroxylases, rescued activity-evoked capillary dilation. The capillary dilation unmasked by inhibiting 20-HETE was dependent on PGE2 activation of EP4 receptors, a vasodilatory pathway previously identified in healthy animals. Cortical 20-HETE levels were increased following MCAO, in agreement with data from stroke patients. Inhibition of {omega}-hydroxylases normalized 20-HETE levels in vivo and increased cerebral blood flow in the peri-infarct cortex. These data identify 20-HETE-dependent vasoconstriction as a mechanism underlying neurovascular coupling impairment after stroke. Our results suggest that the brains energy supply may be significantly reduced after stroke in regions previously believed to be asymptomatic and that {omega}-hydroxylase inhibition may restore healthy neurovascular coupling post-stroke.

neuroscience↗