Alzheimer’s disease: experimental models and reality

Acta Neuropathologica, Journal Year: 2016, Volume and Issue: 133(2), P. 155 - 175

Published: Dec. 26, 2016

Language: Английский

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Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 29, 2019

Abstract The formation of Aβ amyloid fibrils is a neuropathological hallmark Alzheimer’s disease and cerebral angiopathy. However, the structure from brain tissue poorly understood. Here we report purification meningeal their structural analysis with cryo-electron microscopy. We show that these are polymorphic but consist similarly structured protofilaments. Brain derived right-hand twisted peptide fold differs sharply previously analyzed were formed in vitro. These data underscore importance to use patient-derived when investigating basis disease.

Language: Английский

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Cryo-EM structures of amyloid-β 42 filaments from human brains

Science, Journal Year: 2022, Volume and Issue: 375(6577), P. 167 - 172

Published: Jan. 14, 2022

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss memory and other cognitive functions the filamentous assembly Aβ tau in brain. The peptides into that end at residue 42 central event. Yang et al . used electron cryo–electron microscopy to determine structures from brain (see Perspective Willem Fändrich). They identified two types related S-shaped filaments, each consisting identical protofilaments. These will inform development better vitro animal models, inhibitors assembly, imaging agents with increased specificity sensitivity. —SMH

Language: Английский

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The unfolded protein response in neurodegenerative diseases: a neuropathological perspective

Acta Neuropathologica, Journal Year: 2015, Volume and Issue: 130(3), P. 315 - 331

Published: July 25, 2015

The unfolded protein response (UPR) is a stress of the endoplasmic reticulum (ER) to disturbance in folding. so-called ER sensors PERK, IRE1 and ATF6 play central role initiation regulation UPR. accumulation misfolded aggregated proteins common characteristic neurodegenerative diseases. With discovery basic machinery UPR, idea was born that UPR or part its could be involved diseases like Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis prion disease. Over last decade, has been addressed an increasing number studies on neurodegeneration. involvement investigated human neuropathology across different neurological diseases, as well cell mouse models for Studies using disease display discrepancies function during neurodegeneration, which can often attributed differences methodology. In this review, we will address importance investigation brain material interpretation We discuss evidence activation methodology study connection pathology addressed. More recently, recognized target drug therapy treatment prevention by inhibiting specific mediators Several preclinical have shown proof-of-concept approach targeting particular PERK pathway, neurodegeneration yielded paradoxical results. promises held these observations need further support clarification observed between models, increased insight obtained from neuropathology.

Language: Английский

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Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

Alzheimer s Research & Therapy, Journal Year: 2020, Volume and Issue: 12(1)

Published: Aug. 12, 2020

The body of evidence suggesting a causative, initiating role beta amyloid (Aβ) in the pathogenesis Alzheimer's disease (AD) is substantial. Yet, only few anti-amyloid agents have shown meaningful efficacy clinical trials. We evaluated unifying characteristics with positive or biomarker effects long-duration trials and analyzed how pharmacological determine their product profiles. Four potential for near term approval fulfill these criteria: injectable antibodies, aducanumab, gantenerumab, BAN2401, small molecule oral agent, ALZ-801. Aducanumab BAN2401 showed significant on both outcomes; gantenerumab effects, no reported to date; ALZ-801 high-risk population patients homozygous ε4 allele apolipoprotein E gene (APOE4) dose-dependent preservation hippocampal volume. explored properties agents, namely selectivity Aβ oligomers, plasma half-life, brain penetration, time peak exposure, A crucial characteristic shared by ability engage neurotoxic soluble albeit various degrees. partially target while mostly clearing insoluble plaques; preferentially targets protofibrils (large oligomers) over blocks formation oligomers without binding plaques. degree exposure drive magnitude onset efficacy, clearance plaques associated vasogenic edema. Only highest doses aducanumab show modest higher dosing limited increased risk edema, especially APOE4 carriers. These limitations can be avoided, improved that selectively inhibit block toxicity most advanced selective anti-oligomer agent ALZ-801, an optimized prodrug tramiprosate, which demonstrated APOE4/4 AD subjects. fully inhibits Aβ42 at dose, will phase 3 trial early AD. In addition measures, include cerebrospinal fluid, plasma, imaging biomarkers gain further insights into impact progression.

Language: Английский

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Factors affecting the physical stability (aggregation) of peptide therapeutics

Interface Focus, Journal Year: 2017, Volume and Issue: 7(6), P. 20170030 - 20170030

Published: Oct. 20, 2017

The number of biological therapeutic agents in the clinic and development pipeline has increased dramatically over last decade will undoubtedly continue to increase coming years. Despite this fact, there are considerable challenges development, production formulation such biologics particularly with respect their physical stabilities. There many cases where self-association form either amorphous aggregates or highly structured fibrillar species limits use. Here, we review numerous factors that influence stability peptides including both intrinsic external factors, wherever possible illustrating these examples interest. effects sequence, concentration, pH, net charge, excipients, chemical degradation modification, surfaces interfaces, impurities all discussed. In addition, parameters as pressure, temperature, agitation lyophilization described. We provide an overview structures formed, well our current knowledge mechanisms for formation.

Language: Английский

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Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine

International Journal of Molecular Sciences, Journal Year: 2016, Volume and Issue: 17(2), P. 189 - 189

Published: Feb. 2, 2016

Neurodegenerative diseases (NDDs) are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also peripheral organs. These their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora demonstrated different neurodegeneration-related proteins, such amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43), fused sarcoma (FUS), molecular classification NDDs relies on detailed morphological evaluation deposits, distribution brain, correlation to clinical symptoms together specific genetic alterations. A further facet neuropathology-based is fact many deposits show hierarchical involvement regions. This has been shown Alzheimer Parkinson disease some forms tauopathies TDP-43 proteinopathies. The present paper aims summarize current NDDs, focusing most relevant aspects. Since combination proteinopathies frequent, definition novel clusters patients needs considered era precision medicine. Optimally, neuropathological categorizing should translated into vivo detectable biomarkers support better prediction prognosis stratification trials.

Language: Английский

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Aluminium in brain tissue in familial Alzheimer’s disease

Journal of Trace Elements in Medicine and Biology, Journal Year: 2016, Volume and Issue: 40, P. 30 - 36

Published: Dec. 9, 2016

Language: Английский

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Shaping the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases

Ageing Research Reviews, Journal Year: 2019, Volume and Issue: 54, P. 100942 - 100942

Published: Aug. 12, 2019

Language: Английский

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Nrf2: a dark horse in Alzheimer's disease treatment

Ageing Research Reviews, Journal Year: 2020, Volume and Issue: 64, P. 101206 - 101206

Published: Nov. 2, 2020

Language: Английский

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