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 Simvastatin Therapy Attenuates Memory Deficits that Associate to Brain Monocyte Infiltration in Chronic Hypercholesterolemic ApoE-/- Mice

2020 ◽  
Author(s):  
Nicholas Don-Doncow ◽  
Frank Matthes ◽  
Hana Matuskova ◽  
Sara Rattik ◽  
Lotte Vanherle ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cognitive Decline ◽  
Memory Impairment ◽  
Memory Function ◽  
Memory Deficits ◽  
List Type ◽  
Wild Type ◽  
Lowering Therapy ◽  
Neuro Inflammation ◽  
Cardiovascular Therapeutics

AbstractBackground and PurposeMetabolic and cardiovascular disease is the most prevalent disease burden in the world and risk factor for progressive cognitive decline. Evidence associates cardiovascular risk factors to unfavorable systemic and neuro-inflammation and to cognitive decline. Cardiovascular therapeutics (e.g., statins and antihypertensives) possess immune-modulatory functions in parallel to their cholesterol- or blood pressure (BP)-lowering properties. How their ability to modify immune responses affects cognitive function is unknown.Experimental ApproachBy using flow cytometry, Elisa, qPCR, Western blotting and object recognition tasks, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice.Key resultsChronic hypercholesterolemia associated to moderate BP elevations and apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation associated to chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, linking to memory dysfunction. Therapeutic administration of cholesterol-lowering simvastatin reduced BP, systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice. BP-lowering therapy alone (i.e. hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. When administered in combination, it reduced effectiveness of statin therapy in some instances.Conclusions and ImplicationsOur study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment. Cholesterol-lowering therapy provides effectiveness to attenuate memory impairment and inflammatory events and hence, emerges as safe therapeutic strategy to control hypercholesterolemia-associated memory decline.What is already knowncardiovascular risk factors link to unfavorable systemic and neuro-inflammation and to cognitive declinecardiovascular therapeutics possess immune-modulatory functions in parallel to their principle cholesterol- or blood pressure-lowering propertiesWhat this study addslinks chronic hypercholesterolemia in mice to specific immune responses and the development of memory impairmentfavorable outcomes in respect to neuro-inflammation and memory function in hypercholesterolemic mice after statin therapyClinical significanceopens the door for available CVD therapeutics with long-term safety profiles to managing cognitive dysfunctiontargeted monitoring of inflammatory signature in patients with high cardiovascular burden (surrogate biomarker of cognitive decline)

scholarly journals Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

2017 ◽  
Vol 114 (10) ◽  
pp. 2699-2704 ◽  
Author(s):  
S. Pablo Sardi ◽  
Catherine Viel ◽  
Jennifer Clarke ◽  
Christopher M. Treleaven ◽  
Amy M. Richards ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Therapeutic Strategy ◽  
Age Of Onset ◽  
Behavioral Outcomes ◽  
Memory Deficits ◽  
Prolonged Treatment ◽  
Murine Models ◽  
Glucosylceramide Synthase ◽  
The Central Nervous System ◽  
Sporadic Disease

Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson’s disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations inGBAincrease PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model,GbaD409V/D409Vand a A53T–α-synuclein overexpressing model harboring wild-type alleles ofGBA,A53T–SNCAmouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161. Treatment ofGbaD409V/D409Vmice with the GCS inhibitor reduced levels of glucosylceramide and glucosylsphingosine in the central nervous system (CNS), demonstrating target engagement. Remarkably, treatment with GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin, and tau, and improved the associated memory deficits. Similarly, prolonged treatment ofA53T–SNCAmice with GZ667161 reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. The data support the contention that prolonged antagonism of GCS in the CNS can affect α-synuclein processing and improve behavioral outcomes. Hence, inhibition of GCS represents a disease-modifying therapeutic strategy forGBA-related synucleinopathies and conceivably for certain forms of sporadic disease.

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.

Cognitive Deficits in Pediatric Craniopharyngioma: An Updated Review

2021 ◽  
Author(s):  
Abdulrahman Al-Mirza ◽  
Omar Al-Taei ◽  
Tariq Al-Saadi
Keyword(s):  
Systematic Review ◽  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Pediatric Patients ◽  
Memory Deficits ◽  
Neurological Deficits ◽  
Children And Adolescent ◽  
Visual Spatial ◽  
High Incidence ◽  
Standard Tests

AbstractCraniopharyngiomas (CP) are brain tumors that often occur in children and adolescent that results in many neurological and endocrinological disorders. The aim of this systematic review is to provide updated version of studies used to formalize standard tests used for cognitive impairment in pediatric patients with craniopharyngioma. A systematic review was conducted in PubMed, EBSCO, ProQuest, Science Direct, Wiley Online, and Springer to identify studies assessing cognitive impairment in pediatric patients with craniopharyngioma. Academic and learning dysfunctions were reported in seven studies among 41 of 178 patients (23%). Visual–spatial deficits were reported in six studies. Speech and verbal dysfunctions were reported in three studies. Memory deficits were reported in eight studies among 61 of 197 patients (31%). Motor dysfunctions were reported in five studies. Sleep related issues were reported in four studies among 33 of 70 patients (47.1%). Patients with treated pediatric CP demonstrate a high incidence of neurological deficits including cognitive dysfunctions. Academic and learning dysfunctions, visual–spatial deficits, speech and verbal dysfunctions, memory deficits, and sleep-related issues were the most commonly reported cognitive deficits in the present study.

scholarly journals “End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction?

2011 ◽  
Vol 25 (3) ◽  
pp. 445-453 ◽  
Author(s):  
Erin L. Abner ◽  
Richard J. Kryscio ◽  
Frederick A. Schmitt ◽  
Karen S. SantaCruz ◽  
Gregory A. Jicha ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangle ◽  
Preclinical Alzheimer’S Disease ◽  
Tangle Pathology ◽  
End Stage

scholarly journals Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Zhong-he Liu ◽  
Hong-guang Chen ◽  
Pan-feng Wu ◽  
Qing Yao ◽  
Hong-ke Cheng ◽  
...  
Keyword(s):  
Body Weight ◽  
Cerebral Cortex ◽  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Ache Activity ◽  
Memory Deficits ◽  
Test Body ◽  
Morris Water Maze Test ◽  
Diabetic Mice ◽  
Mice Model

Objective. The effects of Flos Puerariae extract (FPE) on cognitive impairment associated with diabetes were assessed in C57BL/6J mice.Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ) for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA) and total cholesterol (TCH) in serum, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and acetylcholinesterase (AChE) activities in cerebral cortex and hippocampus were also measured.Results. Oral administration of FPE significantly improved cognitive deficits in STZ-induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE.Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain.

scholarly journals Green Tea Extract Ameliorates Learning and Memory Deficits in Ischemic Rats via Its Active Component Polyphenol Epigallocatechin-3-gallate by Modulation of Oxidative Stress and Neuroinflammation

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kuo-Jen Wu ◽  
Ming-Tsuen Hsieh ◽  
Chi-Rei Wu ◽  
W. Gibson Wood ◽  
Yuh-Fung Chen
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Learning And Memory ◽  
Green Tea ◽  
Memory Impairment ◽  
Memory Deficits ◽  
Green Tea Extract ◽  
Morris Water Maze Test ◽  
Learning And Memory Deficits ◽  
Tea Extract

Ischemic stroke results in brain damage and behavioral deficits including memory impairment. Protective effects of green tea extract (GTex) and its major functional polyphenol (−)-epigallocatechin gallate (EGCG) on memory were examined in cerebral ischemic rats. GTex and EGCG were administered 1 hr before middle cerebral artery ligation in rats. GTex, EGCG, and pentoxifylline (PTX) significantly improved ishemic-induced memory impairment in a Morris water maze test. Malondialdehyde (MDA) levels, glutathione (GSH), and superoxide dismutase (SOD) activity in the cerebral cortex and hippocampus were increased by long-term treatment with GTex and EGCG. Both compounds were also associated with reduced cerebral infraction breakdown of MDA and GSH in the hippocampus. Inin vitroexperiments, EGCG had anti-inflammatory effects in BV-2 microglia cells. EGCG inhibited lipopolysaccharide- (LPS-) induced nitric oxide production and reduced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV-2 cells. GTex and its active polyphenol EGCG improved learning and memory deficits in a cerebral ischemia animal model and such protection may be due to the reduction of oxidative stress and neuroinflammation.

scholarly journals Sex-specific hippocampus-dependent cognitive deficits and increased neuronal autophagy in DEspR haploinsufficiency in mice

2008 ◽  
Vol 35 (3) ◽  
pp. 316-329 ◽  
Author(s):  
Victoria L. M. Herrera ◽  
Julius L. Decano ◽  
Pia Bagamasbad ◽  
Timothy Kufahl ◽  
Martin Steffen ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Cognitive Performance ◽  
Cognitive Deficits ◽  
Mammalian Target Of Rapamycin ◽  
Male Mice ◽  
Wild Type ◽  
Neuronal Homeostasis ◽  
Subcortical Regions ◽  
Neuronal Autophagy ◽  
Neuronal Vacuolation

Aside from abnormal angiogenesis, dual endothelin-1/VEGF signal peptide-activated receptor deficiency ( DEspR−/−) results in aberrant neuroepithelium and neural tube differentiation, thus elucidating DEspR's role in neurogenesis. With the emerging importance of neurogenesis in adulthood, we tested the hypothesis that nonembryonic-lethal DEspR haploinsufficiency ( DEspR+/−) perturbs neuronal homeostasis, thereby facilitating aging-associated neurodegeneration. Here we show that, in male mice only, DEspR-haploinsufficiency impaired hippocampus-dependent visuospatial and associative learning and induced noninflammatory spongiform changes, neuronal vacuolation, and loss in the hippocampus, cerebral cortex, and subcortical regions, consistent with autophagic cell death. In contrast, DEspR+/− females exhibited better cognitive performance than wild-type females and showed absence of neuropathological changes. Signaling pathway analysis revealed DEspR-mediated phosphorylation of activators of autophagy inhibitor mammalian target of rapamycin (mTOR) and dephosphorylation of known autophagy inducers. Altogether, the data demonstrate DEspR-mediated diametrical, sex-specific modulation of cognitive performance and autophagy, highlight cerebral neuronal vulnerability to autophagic dysregulation, and causally link DEspR haploinsufficiency with increased neuronal autophagy, spongiosis, and cognitive decline in mice.

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