Alzheimer Mechanisms and Therapeutic Strategies

Cell, Journal Year: 2012, Volume and Issue: 148(6), P. 1204 - 1222

Published: March 1, 2012

Language: Английский

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Mechanisms of stress in the brain

Nature Neuroscience, Journal Year: 2015, Volume and Issue: 18(10), P. 1353 - 1363

Published: Sept. 25, 2015

Language: Английский

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Impairment of Glymphatic Pathway Function Promotes Tau Pathology after Traumatic Brain Injury

Journal of Neuroscience, Journal Year: 2014, Volume and Issue: 34(49), P. 16180 - 16193

Published: Dec. 3, 2014

Traumatic brain injury (TBI) is an established risk factor for the early development of dementia, including Alzheimer's disease, and post-traumatic frequently exhibits neurofibrillary tangles comprised aggregates protein tau. We have recently defined a brain-wide network paravascular channels, termed "glymphatic" pathway, along which CSF moves into through parenchyma, facilitating clearance interstitial solutes, amyloid-β, from brain. Here we demonstrate in mice that extracellular tau cleared these pathways. After TBI, glymphatic pathway function was reduced by ∼60%, with this impairment persisting at least 1 month post injury. Genetic knock-out gene encoding astroglial water channel aquaporin-4, importantly involved solute clearance, exacerbated dysfunction after TBI promoted pathology neurodegeneration These findings suggest chronic may be key renders vulnerable to aggregation onset neurodegeneration.

Language: Английский

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Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2012, Volume and Issue: 2(7), P. a006338 - a006338

Published: March 13, 2012

Lennart Mucke1 and Dennis J. Selkoe2 Gladstone Institute of Neurological Disease University California, San Francisco, California 94102 Center for Neurologic Diseases, Harvard Medical School Brigham Women's Hospital, Boston, Massachusetts 02115 Correspondence: lmucke{at}gladstone.ucsf.edu, dselkoe{at}rics.bwh.harvard.edu

Language: Английский

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Network abnormalities and interneuron dysfunction in Alzheimer disease

Nature reviews. Neuroscience, Journal Year: 2016, Volume and Issue: 17(12), P. 777 - 792

Published: Nov. 10, 2016

Language: Английский

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Roles of tau protein in health and disease

Acta Neuropathologica, Journal Year: 2017, Volume and Issue: 133(5), P. 665 - 704

Published: April 6, 2017

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates accompanied by synaptic dysfunction and neural cell death range neurodegenerative disorders, collectively referred to tauopathies. Recent advances our understanding the multiple functions different locations inside outside neurons have revealed novel insights its importance diverse molecular pathways including signalling, plasticity, regulation genomic stability. The present review describes physiological pathophysiological properties how these relate distribution We highlight post-translational modifications tau, which are pivotal defining modulating localisation roles health disease. include discussion other pathologically relevant changes mutation aggregation, aspects impinge on propensity propagate, potentially drive neuronal loss, diseased brain. Finally, we describe cascade events that may be driven dysfunction, impaired axonal transport, alterations synapse mitochondrial function, activation unfolded response defective degradation. It important fully understand attributed since this will provide vital information involvement development pathogenesis Such knowledge enable determination critical should targeted potential therapeutic agents developed for treatment

Language: Английский

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Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2012, Volume and Issue: 2(7), P. a006247 - a006247

Published: March 20, 2012

Tau represents the subunit protein of one major hallmarks Alzheimer disease (AD), neurofibrillary tangles, and is therefore interest as an indicator mechanisms. Many unusual properties can be explained by its nature a natively unfolded protein. Examples are large number structural conformations biochemical modifications (phosphorylation, proteolysis, glycosylation, others), multitude interaction partners (mainly microtubules, but also other cytoskeletal proteins, kinases, phosphatases, motor chaperones, membrane proteins). The pathological aggregation counterintuitive, given high solubility, rationalized short hydrophobic motifs forming β structures. toxic in cell animal models, reversed suppressing expression or inhibitors. This review summarizes some structural, biochemical, biological fibers. Further aspects diagnostic marker therapeutic target, involvement Tau-based diseases, histopathology covered chapters this volume.

Language: Английский

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Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies

Biomolecules, Journal Year: 2016, Volume and Issue: 6(1), P. 6 - 6

Published: Jan. 6, 2016

Abnormal deposition of misprocessed and aggregated proteins is a common final pathway most neurodegenerative diseases, including Alzheimer’s disease (AD). AD characterized by the extraneuronal amyloid β (Aβ) protein in form plaques intraneuronal aggregation microtubule-associated tau filaments. Based on biochemically diverse range pathological proteins, number approaches have been proposed to develop new potential therapeutics. Here we discuss some promising ones: inhibition phosphorylation, proteolysis aggregation, promotion intra- extracellular clearance, stabilization microtubules. We also emphasize need achieve full understanding biological roles post-translational modifications normal tau, as well molecular events responsible for selective neuronal vulnerability pathology its propagation. It concluded that answering key questions relationship between Aβ should lead better nature secondary tauopathies, especially AD, open therapeutic targets strategies.

Language: Английский

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Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Proceedings of the National Academy of Sciences, Journal Year: 2013, Volume and Issue: 110(27)

Published: June 17, 2013

Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism damage remains incompletely understood. Here we describe a pathway for whereby amyloid-β 1–42 peptide (Aβ ) releases, via stimulation α7 nicotinic receptors, excessive amounts glutamate from astrocytes, turn activating extrasynaptic NMDA-type receptors (eNMDARs) to mediate damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced loss, providing hope disease-modifying intervention AD.

Language: Английский

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Tau and tauopathies

Brain Research Bulletin, Journal Year: 2016, Volume and Issue: 126, P. 238 - 292

Published: Sept. 1, 2016

Language: Английский

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