PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia

Abstract The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates the transient shutdown of translation in response to rising levels of misfolded proteins in the endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer’s disease, the tauopathies and prion disorders. These are all characterised by the accumulation of misfolded disease-specific proteins in the brain in association with specific patterns of neuronal loss, but the role of UPR activation in their pathogenesis is unclear. In prion-diseased mice, overactivation of PERK-P/eIF2α-P signalling results in the sustained reduction in global protein synthesis, leading to synaptic failure, neuronal loss and clinical disease. Critically, restoring vital neuronal protein synthesis rates by inhibiting the PERK-eIF2α pathway, both genetically and pharmacologically, prevents prion neurodegeneration downstream of misfolded prion protein accumulation. Here we show that PERK-eIF2α-mediated translational failure is a key process leading to neuronal loss in a mouse model of frontotemporal dementia, where the misfolded protein is a form of mutant tau. rTg4510 mice, which overexpress the P301L tau mutation, show dysregulated PERK signalling and sustained repression of protein synthesis by 6 months of age, associated with onset of neurodegeneration. Treatment with the ...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

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Source: Johns Hopkins University and Health Systems Archive - Category: Nursing Source Type: news
Publication date: Available online 16 October 2019Source: Pharmacology &TherapeuticsAuthor(s): Kazu Nakazawa, Kiran SapkotaAbstractN-methyl-D-aspartate (NMDA) receptor (NMDAR) hypofunction plays a key role in pathophysiology of schizophrenia. Since NMDAR hypofunction has also been reported in autism, Alzheimer’s disease and cognitive dementia, it is crucial to identify the location, timing, and mechanism of NMDAR hypofunction for schizophrenia for better understanding of disease etiology and for novel therapeutic intervention. In this review, we first discuss the shared underlying mechanisms of NMDAR hypofunction...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research
Abstract Galanthamine is an Amaryllidaceae-derived acetylcholinesterase inhibitor used to treat memory impairment in Alzheimer's disease and vascular dementia. There is evidence that galanthamine, in addition to its effects on acetylcholinesterase, may enhance or inhibit brain nicotinic acetylcholine receptors, which could increase or decrease the therapeutic efficacy of galanthamine, respectively. Here, we evaluated the effects of galanthamine and two others Amaryllidaceae acetylcholinesterase inhibitors (haemanthamine and tazettine) analyzed by gas chromatography – mass spectrometry and identified by comparing thei...
Source: Revista Brasileira de Farmacognosia - Category: Drugs & Pharmacology Source Type: research
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Source: WebMD Health - Category: Consumer Health News Source Type: news
Conclusions We found a contextual preventive effect of community-level sports group participation on developing cognitive impairment among older individuals. Furthermore, the benefit may favor sports group participants. Therefore, promoting sports groups in a community setting may be effective as a population-based strategy for the prevention of dementia.
Source: Medicine and Science in Sports and Exercise - Category: Sports Medicine Tags: EPIDEMIOLOGY Source Type: research
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Source: NYT Health - Category: Consumer Health News Authors: Tags: Dementia Source Type: news
CONCLUSION: AD causes impairment of EnA and ExA. Faster reactions by AD participants to the target on the left in VT+s and more accurate reactions to the target on the left in VT-s are in agreement with reports in the literature on the lateralization of visual-spatial attention (VSA) in the right hemisphere. In this study, also in agreement with previous reports, lateralization in AD was noted in favour of the stimuli on the left in ExA. PMID: 31613976 [PubMed - in process]
Source: Turkish Journal of Psychiatry - Category: Psychiatry Authors: Tags: Turk Psikiyatri Derg Source Type: research
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Source: The Journal of Alzheimers Association - Category: Psychiatry Tags: Alzheimers Dement Source Type: research
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Source: SharpBrains - Category: Neuroscience Authors: Tags: Cognitive Neuroscience Health & Wellness Technology aging-population BrainCheck Clinical Psychology cognitive healthcare cognitive-health executive-function memory mental health NeoSensory neurologist Neuropsychology neuroscien Source Type: blogs
THURSDAY, Oct. 17, 2019 -- Could your personality as a teen forecast your risk for dementia a half-century later? Very possibly, say researchers, who found that dementia risk is lower among seniors who were calm, mature and energetic high...
Source: - Daily MedNews - Category: General Medicine Source Type: news
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