scholarly journals Insights into Disease-Associated Tau Impact on Mitochondria

2020 ◽  
Vol 21 (17) ◽  
pp. 6344 ◽  
Author(s):  
Leonora Szabo ◽  
Anne Eckert ◽  
Amandine Grimm
Keyword(s):  
Cognitive Deficits ◽  
Tau Protein ◽  
Frontotemporal Lobar Degeneration ◽  
Therapeutic Interventions ◽  
Mitochondrial Proteins ◽  
Early Event ◽  
Substantial Evidence ◽  
Mitochondrial Functions ◽  
Underlying Mechanisms ◽  
The Brain

Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions.

scholarly journals Tauopathies: One Disease or Many?

2011 ◽  
Vol 38 (4) ◽  
pp. 547-556 ◽  
Author(s):  
Manon Bouchard ◽  
Oksana Suchowersky
Keyword(s):  
Progressive Supranuclear Palsy ◽  
Tau Protein ◽  
Clinical Result ◽  
Frontotemporal Lobar Degeneration ◽  
Disease Process ◽  
Corticobasal Degeneration ◽  
Pathological Lesions ◽  
Abnormal Accumulation ◽  
Genetic Features ◽  
The Brain

Tauopathies are a group of disorders that have in common abnormal accumulation of tau protein in the brain. Although the different tauopathies have long been considered to be separate diseases, it is now clear that progressive supranuclear palsy, corticobasal degeneration and some forms of tau-positive frontotemporal lobar degeneration share clinical, pathological and genetic features. The important overlap between these disorders suggest they may represent different phenotypes of a single disease process, the clinical result depending on the topography of pathological lesions as well as other unknown factors.

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.

DIABETIC ENCEPHALOPATHY IN TYPE 2 DIABETES

2017 ◽  
pp. 52-58
Author(s):  
Van Vy Hau Nguyen ◽  
Hai Thuy Nguyen ◽  
Dinh Toan Nguyen
Keyword(s):  
Type 2 Diabetes ◽  
Cognitive Deficits ◽  
Organ Damage ◽  
Diabetic Encephalopathy ◽  
Downstream Effects ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
The Brain

Type 2 diabetes is a common metabolic disease with a rising global prevalence. It is associated with slowly progressive end-organ damage in the eyes and kidneys, but also in the brain. The latter complication is often referred to as "diabetic encephalopathy" and is characterized by mild to moderate impairments in cognitive functioning. It is also associated with an increased risk of dementia. Diabetic encephalopathies are now accepted complications of diabetes. To date, its pathogenetic mechanisms are largely unclear. They appear to differ in type 1 and type 2 diabetes as to underlying mechanisms and the nature of resulting cognitive deficits. The increased incidence of Alzheimer’s disease in type 2 diabetes is associated with insulin resistance, hyperinsulinemia and hyperglycemia, and commonly accompanying attributes such as hypercholesterolemia, hypertension and obesity. However, cognitive impairement in type 1 diabetes have other differences with type 2 diabetes. The major underlying component here appears to be insulin deficiency with downstream effects on the expression of neurotrophic factors, neurotransmitters, oxidative and apoptotic stressors resulting in defects in neuronal integrity, connectivity and loss commonly occurring in the still developing brain.

Repetitive Head Trauma Induces Chronic Traumatic Encephalopathy by Multiple Mechanisms

2020 ◽  
Vol 40 (04) ◽  
pp. 430-438 ◽  
Author(s):  
Jonathan D. Cherry ◽  
Katharine J. Babcock ◽  
Lee E. Goldstein
Keyword(s):  
Cognitive Deficits ◽  
Tau Protein ◽  
Chronic Traumatic Encephalopathy ◽  
Biomechanical Properties ◽  
Ice Hockey ◽  
American Football ◽  
Head Impacts ◽  
Blast Exposure ◽  
Hyperphosphorylated Tau Protein ◽  
The Brain

AbstractExposure to repetitive neurotrauma increases lifetime risk for developing progressive cognitive deficits, neurobehavioral abnormalities, and chronic traumatic encephalopathy (CTE). CTE is a tau protein neurodegenerative disease first identified in boxers and recently described in athletes participating in other contact sports (notably American football, ice hockey, rugby, and wrestling) and in military veterans with blast exposure. Currently, CTE can only be diagnosed by neuropathological examination of the brain after death. The defining diagnostic lesion of CTE consists of patchy perivascular accumulations of hyperphosphorylated tau protein that localize in the sulcal depths of the cerebral cortex. Neuronal abnormalities, axonopathy, neurovascular dysfunction, and neuroinflammation are triggered by repetitive head impacts (RHIs) and likely act as catalysts for CTE pathogenesis and progression. However, the specific mechanisms that link RHI to CTE are unknown. This review will explore two important areas of CTE pathobiology. First, we will review what is known about the biomechanical properties of RHI that initiate CTE-related pathologies. Second, we will provide an overview of key features of CTE neuropathology and how these contribute to abnormal tau hyperphosphorylation, accumulation, and spread.

α-synuclein regulation of dopamine transporter

2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Brittany Butler ◽  
Kaustuv Saha ◽  
Habibeh Khoshbouei
Keyword(s):  
Dopamine Transporter ◽  
Neurological Disorders ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Stable Complex ◽  
Early Event ◽  
Acid Protein ◽  
Neuronal Plasma Membrane ◽  
The Brain ◽  
Amino Acid Protein

AbstractThe development of effective therapeutic interventions for neurodegeneration requires a better understanding of the early events that precede neuronal loss. Recent work in various disease models has begun to emphasize the significance of presynaptic dysfunction as an early event that occurs before manifestation of neurological disorders. Dysregulation of dopamine (DA) homeostasis is implicated in neurodegenerative diseases, drug addiction, and neuropsychiatric disorders. The neuronal plasma membrane dopamine transporter (DAT) is essential for the maintenance of DA homeostasis in the brain. α-synuclein is a 140-amino acid protein that forms a stable complex with DAT and is linked to the pathogenesis of neurodegenerative disease. In this review we will examine the prevailing hypotheses for α-synuclein-regulation of DAT biology.

scholarly journals Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 692 ◽  
Author(s):  
Noemí Rueda Revilla ◽  
Carmen Martínez-Cué
Keyword(s):  
Oxidative Stress ◽  
Clinical Trials ◽  
Down Syndrome ◽  
Cognitive Dysfunction ◽  
Cognitive Deficits ◽  
Later Life ◽  
Chromosome 21 ◽  
Therapeutic Interventions ◽  
Early Event ◽  
Preclinical Studies

There is currently no effective pharmacological therapy to improve the cognitive dysfunction of individuals with Down syndrome (DS). Due to the overexpression of several chromosome 21 genes, cellular and systemic oxidative stress (OS) is one of the most important neuropathological processes that contributes to the cognitive deficits and multiple neuronal alterations in DS. In this condition, OS is an early event that negatively affects brain development, which is also aggravated in later life stages, contributing to neurodegeneration, accelerated aging, and the development of Alzheimer’s disease neuropathology. Thus, therapeutic interventions that reduce OS have been proposed as a promising strategy to avoid neurodegeneration and to improve cognition in DS patients. Several antioxidant molecules have been proven to be effective in preclinical studies; however, clinical trials have failed to show evidence of the efficacy of different antioxidants to improve cognitive deficits in individuals with DS. In this review we summarize preclinical studies of cell cultures and mouse models, as well as clinical studies in which the effect of therapies which reduce oxidative stress and mitochondrial alterations on the cognitive dysfunction associated with DS have been assessed.

scholarly journals Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Yanmin Chang ◽  
Yi Yao ◽  
Rong Ma ◽  
Zemin Wang ◽  
Junjie Hu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cognitive Deficits ◽  
Tau Protein ◽  
Animal Studies ◽  
Inflammatory Responses ◽  
Hyperphosphorylated Tau ◽  
Behavioral Deficits ◽  
Synaptic Loss ◽  
Underlying Mechanisms ◽  
P301s Mutation

Alzheimer’s disease (AD) is a destructive and burdensome neurodegenerative disease, one of the most common characteristics of which are neurofibrillary tangles (NFTs) that are composed of abnormal tau protein. Animal studies have suggested that dl-3-n-butylphthalide (dl-NBP) alleviates cognitive impairment in mouse models of APP/PS1 and SAMP8. However, the underlying mechanisms related to this remain unclear. In this study, we examined the effects of dl-NBP on learning and memory in P301S transgenic mice, which carry the human tau gene with the P301S mutation. We found that dl-NBP supplementation effectively improved behavioral deficits and rescued synaptic loss in P301S tau transgenic mice, compared with vehicle-treated P301S mice. Furthermore, we also found that it markedly inhibited the hyperphosphorylated tau at the Ser262 site and decreased the activity of MARK4, which was associated with tau at the Ser262 site. Finally, dl-NBP treatment exerted anti-inflammatory effects and reduced inflammatory responses in P301S mice. In conclusion, our results provide evidence that dl-NBP has a promising potential for the therapy of tauopathies, including AD.

scholarly journals Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration

2018 ◽  
Author(s):  
Grace I Hallinan ◽  
Mariana Vargas-Caballero ◽  
Jonathan West ◽  
Katrin Deinhardt
Keyword(s):  
Cell Death ◽  
Axonal Transport ◽  
Tau Protein ◽  
Neuronal Death ◽  
Early Event ◽  
Neuronal Dysfunction ◽  
Tau Pathology ◽  
Functional Consequences ◽  
Tau Aggregation ◽  
The Brain

AbstractIn Alzheimer’s disease, misfolded tau protein propagates through the brain in a prion-like manner along connected circuits. Tauopathy correlates with significant neuronal death, but the links between tau aggregation, propagation, neuronal dysfunction and death remain poorly understood, and the direct functional consequences for the neuron containing the tau aggregates are unclear. Here, by monitoring individual neurons within a minimal circuit, we demonstrate that misfolded tau efficiently spreads from presynaptic to postsynaptic neurons. Within postsynaptic cells, tau aggregates initially in distal axons, while proximal axons remain free of tau pathology. In the presence of tau aggregates neurons display axonal transport deficits, but remain viable and electrically competent. This shows that misfolded tau species are not immediately toxic to neurons, and suggests that propagation of misfolded tau is an early event in disease, occurring prior to neuronal dysfunction and cell death.

scholarly journals Modulating brain networks associated with cognitive deficits in Parkinson’s disease

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Iman Beheshti ◽  
Ji Hyun Ko
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Deficits ◽  
Brain Networks ◽  
Brain Network ◽  
Clinical Settings ◽  
Pharmacological Interventions ◽  
Future Directions ◽  
Underlying Mechanisms ◽  
The Brain

AbstractParkinson’s disease (PD) is a relatively well characterised neurological disorder that primarily affects motor and cognitive functions. This paper reviews on how transcranial direct current stimulation (tDCS) can be used to modulate brain networks associated with cognitive deficits in PD. We first provide an overview of brain network abnormalities in PD, by introducing the brain network modulation approaches such as pharmacological interventions and brain stimulation techniques. We then present the potential underlying mechanisms of tDCS technique, and specifically highlight how tDCS can be applied to modulate brain network abnormality associated with cognitive dysfunction among PD patients. More importantly, we address the limitations of existing studies and suggest possible future directions, with the aim of helping researchers to further develop the use of tDCS technique in clinical settings.

Morphological Changes in the Brain of Acutely Ill and Weight-Recovered Patients with Anorexia Nervosa

2014 ◽  
Vol 42 (1) ◽  
pp. 7-18 ◽  
Author(s):  
Jochen Seitz ◽  
Katharina Bühren ◽  
Georg G. von Polier ◽  
Nicole Heussen ◽  
Beate Herpertz-Dahlmann ◽  
...  
Keyword(s):  
Anorexia Nervosa ◽  
Cognitive Deficits ◽  
Time Course ◽  
Morphological Changes ◽  
Meta Analysis ◽  
Short Term ◽  
Clinical Prognosis ◽  
Qualitative Review ◽  
Brain Changes ◽  
The Brain

Objective: Acute anorexia nervosa (AN) leads to reduced gray (GM) and white matter (WM) volume in the brain, which however improves again upon restoration of weight. Yet little is known about the extent and clinical correlates of these brain changes, nor do we know much about the time-course and completeness of their recovery. Methods: We conducted a meta-analysis and a qualitative review of all magnetic resonance imaging studies involving volume analyses of the brain in both acute and recovered AN. Results: We identified structural neuroimaging studies with a total of 214 acute AN patients and 177 weight-recovered AN patients. In acute AN, GM was reduced by 5.6% and WM by 3.8% compared to healthy controls (HC). Short-term weight recovery 2–5 months after admission resulted in restitution of about half of the GM aberrations and almost full WM recovery. After 2–8 years of remission GM and WM were nearly normalized, and differences to HC (GM: –1.0%, WM: –0.7%) were no longer significant, although small residual changes could not be ruled out. In the qualitative review some studies found GM volume loss to be associated with cognitive deficits and clinical prognosis. Conclusions: GM and WM were strongly reduced in acute AN. The completeness of brain volume rehabilitation remained equivocal.

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