Faculty Opinions recommendation of [CONFERENCE PRESENTATION]: Aberrant microglial activation contributes to cognitive deficits in Alzheimer.

2011 ◽  
Author(s):  
W Sue Griffin
Keyword(s):  
Cognitive Deficits ◽  
Microglial Activation

scholarly journals CX3CR1 Protein Signaling Modulates Microglial Activation and Protects against Plaque-independent Cognitive Deficits in a Mouse Model of Alzheimer Disease

2011 ◽  
Vol 286 (37) ◽  
pp. 32713-32722 ◽  
Author(s):  
Seo-Hyun Cho ◽  
Binggui Sun ◽  
Yungui Zhou ◽  
Tiina M. Kauppinen ◽  
Brian Halabisky ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Mouse Model ◽  
Cognitive Deficits ◽  
Microglial Activation ◽  
Protein Signaling

scholarly journals Low-Level Laser Light Therapy Improves Cognitive Deficits and Inhibits Microglial Activation after Controlled Cortical Impact in Mice

2012 ◽  
Vol 29 (2) ◽  
pp. 408-417 ◽  
Author(s):  
Jugta Khuman ◽  
Jimmy Zhang ◽  
Juyeon Park ◽  
James D. Carroll ◽  
Chad Donahue ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Microglial Activation ◽  
Laser Light ◽  
Light Therapy ◽  
Controlled Cortical Impact ◽  
Low Level ◽  
Low Level Laser ◽  
Level Laser ◽  
Cortical Impact

scholarly journals URMC-099 Prophylaxis Repairs Hippocampal Vascular Damage in an Orthopedic Model of Delirium Superimposed on Dementia

2021 ◽  
Author(s):  
Patrick Miller-Rhodes ◽  
Herman Li ◽  
Ravikanth Velagapudi ◽  
Niccolo Terrando ◽  
Harris A Gelbard
Keyword(s):  
Cognitive Deficits ◽  
Microglial Activation ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Endothelial Activation ◽  
Surgical Trauma ◽  
Data Link ◽  
Synapse Loss ◽  
The Brain ◽  
Delirium Superimposed On Dementia

Systemic perturbations can drive a neuroimmune cascade after surgical trauma, including affecting the blood-brain barrier (BBB), activating microglia, and contributing to cognitive deficits such as delirium. Delirium superimposed on dementia (DSD) is a particularly debilitating complication that renders the brain further vulnerable to neuroinflammation and neurodegeneration, albeit these molecular mechanisms remain poorly understood. Here we have used an orthopedic model of tibial fracture/fixation in APPSwDI/mNos2-/- AD (CVN-AD) mice to investigate relevant pathogenetic mechanisms underlying DSD. We conducted the present study in 6 months-old CVN-AD mice, an age at which we speculated amyloid-β pathology had not saturated BBB and neuroimmune functioning. We found that URMC-099, our brain-penetrant anti-inflammatory neuroprotective drug, prevented inflammatory endothelial activation, synapse loss, and microglial activation in our DSD model. Taken together, our data link post-surgical endothelial activation, microglial MafB immunoreactivity, and synapse loss as key substrates for DSD, all of which can be reversed by URMC-099.

scholarly journals Microglial Activation Contributes to Cognitive Impairments in Rotenone-induced Mouse Parkinson’s Disease Model

2020 ◽  
Author(s):  
Dongdong Zhang ◽  
Sheng Li ◽  
Liyan Hou ◽  
Lu Jing ◽  
Zhengzheng Ruan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cognitive Decline ◽  
Passive Avoidance ◽  
Cognitive Performance ◽  
Cognitive Deficits ◽  
Water Maze ◽  
Microglial Activation ◽  
Cognitive Impairments ◽  
Synaptic Loss

Abstract BackgroundCognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the life quality of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by over-activated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using rotenone-induced mouse PD model. Methods: To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by morris water maze, objective recognition and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation and apoptosis were determined by immunohistochemistry, Western blot or immunofluorescence staining. The gene expressions of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased abilities of novel objective recognition, passive avoidance, as well as morris water maze performance compared with vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. Time course study revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 or minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in combined PLX3397 or minocycline and rotenone-treated mice compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. ConclusionsTaken together, our findings suggested that microglial activation contributed to cognitive impairments in rotenone-induced mouse PD model via neuroinflammation, oxidative stress and apoptosis, providing novel insight for the immunopathogensis of cognitive deficits in PD.

scholarly journals Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph Flores ◽  
Anastasia Noël ◽  
Bénédicte Foveau ◽  
Olivier Beauchet ◽  
Andréa C. LeBlanc
Keyword(s):  
Alzheimer Disease ◽  
Cognitive Deficits ◽  
Microglial Activation ◽  
Symptomatic Treatment ◽  
Memory Deficits ◽  
Brain Inflammation ◽  
Therapeutic Interventions ◽  
Wild Type ◽  
Caspase 1 ◽  
Beta Peptide

Abstract Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APPSw/Ind) J20 and wild-type mice with VX-765 delays both APPSw/Ind- and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.

scholarly journals When the air hits your brain: decreased arterial pulsatility after craniectomy leading to impaired glymphatic flow

2020 ◽  
Vol 133 (1) ◽  
pp. 210-223 ◽  
Author(s):  
Benjamin A. Plog ◽  
Nanhong Lou ◽  
Clifford A. Pierre ◽  
Alex Cove ◽  
H. Mark Kenney ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Brain Function ◽  
Microglial Activation ◽  
Ex Vivo ◽  
Brain Parenchyma ◽  
Neurological Function ◽  
Neurosurgical Procedures ◽  
Two Photon ◽  
Syndrome Of The Trephined

OBJECTIVECranial neurosurgical procedures can cause changes in brain function. There are many potential explanations, but the effect of simply opening the skull has not been addressed, except for research into syndrome of the trephined. The glymphatic circulation, by which CSF and interstitial fluid circulate through periarterial spaces, brain parenchyma, and perivenous spaces, depends on arterial pulsations to provide the driving force for bulk flow; opening the cranial cavity could dampen this force. The authors hypothesized that a craniectomy, without any other pathological insult, is sufficient to alter brain function due to reduced arterial pulsatility and decreased glymphatic flow. Furthermore, they postulated that glymphatic impairment would produce activation of astrocytes and microglia; with the reestablishment of a closed cranial compartment, the glymphatic impairment, astrocytic/microglial activation, and neurobehavioral decline caused by opening the cranial compartment might be reversed.METHODSUsing two-photon in vivo microscopy, the pulsatility index of cortical vessels was quantified through a thinned murine skull and then again after craniectomy. Glymphatic influx was determined with ex vivo fluorescence microscopy of mice 0, 14, 28, and 56 days following craniectomy or cranioplasty; brain sections were immunohistochemically labeled for GFAP and CD68. Motor and cognitive performance was quantified with rotarod and novel object recognition tests at baseline and 14, 21, and 28 days following craniectomy or cranioplasty.RESULTSPenetrating arterial pulsatility decreased significantly and bilaterally following unilateral craniectomy, producing immediate and chronic impairment of glymphatic CSF influx in the ipsilateral and contralateral brain parenchyma. Craniectomy-related glymphatic dysfunction was associated with an astrocytic and microglial inflammatory response, as well as with the development of motor and cognitive deficits. Recovery of glymphatic flow preceded reduced gliosis and return of normal neurological function, and cranioplasty accelerated this recovery.CONCLUSIONSCraniectomy causes glymphatic dysfunction, gliosis, and changes in neurological function in this murine model of syndrome of the trephined.

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