Poststroke cognitive impairment and hippocampal neurovascular remodeling: the impact of diabetes and sex

Abstract

Diabetes increases the risk and severity of cognitive impairment, especially after ischemic stroke. Pathological remodeling of the cerebrovasculature has been postulated to contribute to poor neuronal repair and worsened cognitive deficits in diabetes. However, little is known about the effect of diabetes on the vascularization of hippocampus, a domain critical to memory and learning. Therefore we had two aims for this study: 1) to determine the impact of diabetes on hippocampal neurovascular remodeling and the resulting cognitive impairment after stroke using two models with varying disease severity, and 2) to compare the effects of ischemia on hippocampal neurovascular injury in diabetic males and females. Stroke was induced by middle cerebral artery occlusion (MCAO) by either the suture or embolic method in control and diabetic age-matched male and female Wistar rats. Hippocampal neuronal density, vascular architecture, and microglial activation as well as cognitive outcomes were measured. Embolic MCAO induced greater neuronal degeneration, pathological vascularization, microglial activation and cognitive impairment in diabetes as compared to control animals or 60 min MCAO. While diabetic males had lower neuronal density at baseline, diabetic females had more neurodegeneration after stroke. Control animals recovered cognitive function by D14 after stroke, diabetic animals showed deficits regardless of sex. These results suggest that mechanisms underlying cognitive decline in diabetes may differ in males and females and provide further insight to the impact of diabetes on stroke severity and post-stroke cognitive impairment.

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

“…However, this early antiinflammatory state is absent when similar experiments are conducted in diabetic animals and this is associated with impaired white matter repair and long-term functional deficits [11]. We also showed that diabetes, as a chronic inflammatory disease, increases the number of activated ameboid microglia and worsens cognitive outcomes of stroke [12,13]. These studies suggest that the inflammatory status of microglia can be modulated by the microenvironment [14].…”

“…The high degree of macrophage infiltration in the diabetic animals brings into question the blood brain (BBB) integrity. Utilizing the same HFD/STZ model reported here, our lab has previously shown that diabetic animals have a compromised BBB that persists 14 days poststroke [13]. This brought into question whether the CSF1R silencing would improve or exacerbate the compromised BBB.…”

“…Sustained neuroinflammation is a critical pathogenic feature of cognitive impairment due to Alzheimer's disease and related dementias [29]. We have reported that sustained microglial activation that occurs in both hypertensive [30] and diabetic stroke models is associated with progressive post-stroke cognitive impairment [13,16]. These findings led us to postulate that microglia are responsible for the progression of cognitive impairment after stroke in diabetes.…”

C1q/TNF‐related protein 9: A novel therapeutic target in ischemic stroke?

“…Besides, obese Zucker rats whose middle cerebral arteries underwent structural remodeling had greater cerebral injury after cerebral ischemia (Osmond, Mintz, Dalton, & Stepp, ). In addition, pathological remodeling of cerebrovasculature has been proved to contribute to poor neuronal repair and worsened cognitive deficits in rats with diabetic stroke (Ward et al, ). In clinical researches, pathological vascular remodeling has been used as an approach and an indicator to evaluate the etiology (Sun & Yuan, ), risk stratification (Wu et al, ) and therapeutic efficacy (Abraham et al, ).…”

Praeruptorin C alleviates cognitive impairment in Type 2 diabetic mice through restoring PI3K/AKT/ GSK3β pathway

“…Diabetic encephalopathy (DE), one of the main complications of DM, is characterized by brain infarcts [3], brain atrophy in cortex and hippocampal volume [4], cerebrovascular disfunction and morphological change [5], and impairment of synaptic plasticity [6]. Notably, an increasing amount of studies have revealed the link between diabetes and neurodegenerative disorders, such as Alzheimer's disease (AD), with changes in cognitive impairment [7][8][9].…”