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

Abstract

Introduction: Unfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2-6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation in diabetes to poor functional outcomes and exacerbated cognitive impairment, also known as post-stroke cognitive impairment (PSCI). Although we have shown that the development of PSCI in diabetes is associated with the upregulation and the activation of pro-inflammatory microglia, we have not established direct causation between the two. To this end, we evaluated the role of microglia in the development of PSCI.Methods: At 13 weeks of age, diabetic animals received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles targeting the colony stimulating factor 1 receptor (CSF1R). After 14 days, animals were subjected to 60 min middle cerebral artery occlusion (MCAO) or sham surgery. Adhesive removal task (ART), novel object recognition (NOR), and 2-trial Y-maze were utilized to evaluate sensorimotor and cognitive function. Tissue from freshly harvested brains was analyzed by flow cytometry and immunohistochemistry.Results: CSF1R silencing resulted in a 94% knockdown of residential microglia to relieve inflammation and improve myelination of white matter in the brain. This prevented cognitive decline in diabetic animals. Conclusion: Microglial activation after stroke in diabetes may be causally related to the development of delayed neurodegeneration and PSCI.

Microglial activation contributes to cognitive impairments in rotenone-induced mouse Parkinson’s disease model

“…Inflammation has long been found to be inversely correlated cognitive decline [ 20 , 49 ]. Increasing evidence suggested that activated microglia is a key causative factor in inflammation-mediated neurodegeneration and behavioral deficits [ 50 ]. Dysregulated microglial activation is reported to be able to increase pathological protein aggregation and impair synaptic pruning and neuron plasticity in key brain regions subserving cognition [ 51 , 52 ].…”

Pterostilbene Attenuates Cocultured BV-2 Microglial Inflammation-Mediated SH-SY5Y Neuronal Oxidative Injury via SIRT-1 Signalling

“…Inflammation is considered to play a pivotal part in diverse diseases, including neurodegenerative diseases [1,2], brain trauma [3], stroke [4], infection [5], and even mental disorders [6], in the central nervous system (CNS). Accumulating evidences suggest that microglia, the resident innate immune cells, which accounts for 10% of CNS cells, are the active participants in the pathophysiological processes related to these neuroinflammatory diseases [7].…”

“…However, microglia dysfunction in pathological conditions and promote neurotoxicity through excessive inflammatory cytokine release [8]. Studies have shown that microgliamediated inflammation and production of proinflammatory factors, including interleukins (ILs) and tumour necrosis factor (TNF) or noninflammatory factors, such as superoxide ions, are important pathogenic bases of neurological diseases, such as intracranial infections, stroke, trauma, and Alzheimer's disease (AD) [1][2][3][4][5][6]. These overly released superoxide and cytokines trigger the oxidative injury and apoptosis of neurons.…”

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

“…Microglia are the resident immune cells of the central nervous system (CNS) and represent approximately 10% of CNS cells in a healthy brain and spinal cord. These cells have recently attracted renewed interest because of the critical role they play in major brain diseases, such as dementia [ 1 ], stroke [ 2 ], and brain tumours [ 3 ]. In brain disease or upon immune challenge, resting microglia adopt programmatic changes associated with the release of cytokines and chemokines.…”