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 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 Electro-acupuncture Alleviates METH Withdrawal-induced Spatial Memory Deficits by Restoring Astrocyte-drived Glutamate Uptake in dCA1

2020 ◽  
Author(s):  
Pengbo Shi ◽  
Zhaosu Li ◽  
Xing Xu ◽  
Jiaxun Nie ◽  
Dekang Liu ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Cognitive Deficits ◽  
Glutamate Uptake ◽  
Cognitive Disorders ◽  
Memory Deficits ◽  
Therapeutic Interventions ◽  
Therapeutic Effects ◽  
Non Invasive ◽  
The Brain

ABSTRACTMethamphetamine (METH) is frequently abused drug and produces cognitive deficits. METH could induce hyper-glutamatergic state in the brain, which could partially explain METH-related cognitive deficits, but the synaptic etiology remains incompletely understood. To address this issue, we explored the role of dCA1 tripartite synapses and the potential therapeutic effects of electro-acupuncture (EA) in the development of METH withdrawal-induced spatial memory deficits in mice. We found that METH withdrawal weakened astrocytic capacity of glutamate (Glu) uptake, but failed to change Glu release from dCA3, which lead to hyper-glutamatergic excitotoxicity at dCA1 tripartite synapses. By restoring the astrocytic capacity of Glu uptake, EA treatments suppressed the hyper-glutamatergic state and normalized the excitability of postsynaptic neuron in dCA1, finally alleviated spatial memory deficits in METH withdrawal mice. These findings indicate that astrocyte at tripartite synapses might be a key target for developing therapeutic interventions against METH-associated cognitive disorders, and EA represent a promising non-invasive therapeutic strategy for the management of drugs-caused neurotoxicity.

scholarly journals Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy

2019 ◽  
Vol 28 (19) ◽  
pp. 3255-3269 ◽  
Author(s):  
Emily J Koller ◽  
Elsa Gonzalez De La Cruz ◽  
Timothy Machula ◽  
Kristen R Ibanez ◽  
Wen-Lang Lin ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Memory Impairment ◽  
Behavioral Outcomes ◽  
Memory Deficits ◽  
Wild Type ◽  
Robust Model ◽  
Physiological Properties ◽  
Targeted Expression ◽  
Tangle Pathology ◽  
End Stage

Abstract Understanding the biological functions of tau variants can illuminate differential etiologies of Alzheimer’s disease (AD) and primary tauopathies. Though the end-stage neuropathological attributes of AD and primary tauopathies are similar, the etiology and behavioral outcomes of these diseases follow unique and divergent trajectories. To study the divergent physiological properties of tau variants on a uniform immunogenetic background, we created somatic transgenesis CNS models of tauopathy utilizing neonatal delivery of adeno-associated viruses expressing wild-type (WT) or mutant tau in non-transgenic mice. We selected four different tau variants—WT tau associated with AD, P301L mutant tau associated with frontotemporal dementia (FTD), S320F mutant tau associated with Pick’s disease and a combinatorial approach using P301L/S320F mutant tau. CNS-targeted expression of WT and P301L mutant tau results in robust tau hyperphosphorylation without tangle pathology, gradually developing age-progressive memory deficits. In contrast, the S320F variant, especially in combination with P301L, produces an AD-type tangle pathology, focal neuroinflammation and memory impairment on an accelerated time scale. Using the doubly mutated P301L/S320F tau variant, we demonstrate that combining different mutations can have an additive effect on neuropathologies and associated co-morbidities, possibly hinting at involvement of unique functional pathways. Importantly, we also show that overexpression of wild-type tau as well as an FTD-associated tau variant can lead to cognitive deficits even in the absence of tangles. Together, our data highlights the synergistic neuropathologies and associated cognitive and synaptic alterations of the combinatorial tau variant leading to a robust model of tauopathy.

scholarly journals High Systolic Blood Pressure Induces Cerebral Microvascular Endothelial Dysfunction, Neurovascular Unit Damage, and Cognitive Decline in Mice

Hypertension ◽  
2019 ◽  
Vol 73 (1) ◽  
pp. 217-228 ◽  
Author(s):  
Olivia de Montgolfier ◽  
Anthony Pinçon ◽  
Philippe Pouliot ◽  
Marc-Antoine Gillis ◽  
Jonathan Bishop ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Cognitive Decline ◽  
Vascular Dementia ◽  
Mechanical Stress ◽  
Neurovascular Unit ◽  
Brain Inflammation ◽  
Transverse Aortic Constriction ◽  
Wild Type ◽  
Aortic Constriction ◽  
Microvascular Endothelial

A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculation: in wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction–induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.

G-lymphatic, vascular and immune pathways for Aβ clearance cascade and therapeutic targets for Alzheimer’s disease

2020 ◽  
Vol 23 ◽  
Author(s):  
Saurav Chakraborty ◽  
Jyothsna ThimmaReddygari ◽  
Divakar Selvaraj
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Complement System ◽  
Therapeutic Targets ◽  
Neuronal Cell ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Beta Peptide ◽  
Immune Pathways

The Alzheimer disease is a age related neurodegenerative disease. The factors causing alzheimer disease are numerous. Research on humans and rodent models predicted various causative factors involved in Alzheimer disease progression. Among them, neuroinflammation, oxidative stress and apoptosis play a major role because of accumulation of extracellular amyloid beta peptides. Here, the clearance of amyloid beta peptide plays a major role because of the imbalance in the production and clearance of the amyloid beta peptide. Additionally, neuroinflammation by microglia, astrocytes, cytokines, chemokines and the complement system also have a major role in Alzheimer disease. The physiological clearance pathways involved in amyloid beta peptide are glymphatic, vascular and immune pathways. Amyloid precursor protein, low density lipoprotein receptor-related protein 1, receptor for advanced glycation end product, apolipoprotein E, clusterin, aquaporin 4, auto-antibodies, complement system, cytokines and microglia are involved in amyloid beta peptide clearance pathways across the blood brain barrier. The plaque formation in the brain by alternative splicing of amyloid precursor protein and production of misfolded protein results in amyloid beta agglomeration. This insoluble amyloid beta leads to neurodegenerative cascade and neuronal cell death occurs. Studies had shown disturbed sleep may be a risk factor for dementia and cognitive decline. In this review, the therapeutic targets for alzheimer disease via focussing on pathways for amyloid beta clearance are discussed.

scholarly journals A coimmunization vaccine of Aβ42 ameliorates cognitive deficits without brain inflammation in an Alzheimer’s disease model

2014 ◽  
Vol 6 (3) ◽  
pp. 26 ◽  
Author(s):  
Shuang Wang ◽  
Yang Yu ◽  
Shuang Geng ◽  
Dongmei Wang ◽  
Li Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Deficits ◽  
Disease Model ◽  
Brain Inflammation

scholarly journals Sepsis Associated Encephalopathy

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Neera Chaudhry ◽  
Ashish Kumar Duggal
Keyword(s):  
Critically Ill ◽  
Clinical Presentation ◽  
Neurological Complication ◽  
Symptomatic Treatment ◽  
Endothelial Activation ◽  
The Body ◽  
Brain Inflammation ◽  
Deep Coma ◽  
Critically Ill Patient ◽  
Cns Infection

Sepsis associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis. It is characterized by diffuse brain dysfunction secondary to infection elsewhere in the body without overt CNS infection. The pathophysiology of SAE is complex and multifactorial including a number of intertwined mechanisms such as vascular damage, endothelial activation, breakdown of the blood brain barrier, altered brain signaling, brain inflammation, and apoptosis. Clinical presentation of SAE may range from mild symptoms such as malaise and concentration deficits to deep coma. The evaluation of cognitive dysfunction is made difficult by the absence of any specific investigations or biomarkers and the common use of sedation in critically ill patients. SAE thus remains diagnosis of exclusion which can only be made after ruling out other causes of altered mentation in a febrile, critically ill patient by appropriate investigations. In spite of high mortality rate, management of SAE is limited to treatment of the underlying infection and symptomatic treatment for delirium and seizures. It is important to be aware of this condition because SAE may present in early stages of sepsis, even before the diagnostic criteria for sepsis can be met. This review discusses the diagnostic approach to patients with SAE along with its epidemiology, pathophysiology, clinical presentation, and differential diagnosis.

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