Alzheimer’s disease – the journey of a healthy brain into organ failure DOI Creative Commons
Todd E. Golde

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Март 5, 2022

As the most common dementia, Alzheimer's disease (AD) exacts an immense personal, societal, and economic toll. AD was first described at neuropathological level in early 1900s. Today, we have mechanistic insight into select aspects of pathogenesis ability to clinically detect diagnose underlying pathologies living patients. These insights demonstrate that is a complex, insidious, degenerative proteinopathy triggered by Aβ aggregate formation. Over time pathology drives neurofibrillary tangle (NFT) pathology, dysfunction virtually all cell types brain, ultimately, overt neurodegeneration. Yet, large gaps our knowledge pathophysiology huge unmet medical need remain. Though largely conceptualize as aging, heritable non-heritable factors impact brain physiology, either continuously or specific points during lifespan, thereby alter risk for devolvement AD. Herein, I describe lifelong journey healthy from birth death with AD, while acknowledging many remain regarding understanding pathogenesis. To ensure current lexicon surrounding changes inevitable, incurable, poorly manageable preventable, curable, must address these gaps, develop therapies bigger on clinical symptoms progression use interventions appropriate stage disease.

Язык: Английский

Alzheimer disease DOI
David S. Knopman, Hélène Amieva, Ronald C. Petersen

и другие.

Nature Reviews Disease Primers, Год журнала: 2021, Номер 7(1)

Опубликована: Май 13, 2021

Язык: Английский

Процитировано

1572
Down syndrome DOI
Stylianos E. Antonarakis, Brian G. Skotko, Michael S. Rafii

и другие.

Nature Reviews Disease Primers, Год журнала: 2020, Номер 6(1)

Опубликована: Фев. 6, 2020

Язык: Английский

Процитировано

647
Amyloid-β-independent regulators of tau pathology in Alzheimer disease DOI
Rik van der Kant, Lawrence S.B. Goldstein, Rik Ossenkoppele

и другие.

Nature reviews. Neuroscience, Год журнала: 2019, Номер 21(1), С. 21 - 35

Опубликована: Ноя. 28, 2019

Язык: Английский

Процитировано

454
Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains DOI Creative Commons
Loan Vaillant-Beuchot, Arnaud Mary, Raphaëlle Pardossi‐Piquard

и другие.

Acta Neuropathologica, Год журнала: 2020, Номер 141(1), С. 39 - 65

Опубликована: Окт. 20, 2020

Abstract Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger Alzheimer’s disease (AD) pathology. Altered mitochondrial homeostasis is considered early event in AD development. However, specific contribution APP-CTFs structure, function, and mitophagy defects remains be established. Here, we demonstrate neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or β-secretase-derived APP-CTF fragment (C99) combined with β- γ-secretase inhibition, accumulation independently Aβ triggers excessive morphology alteration (i.e., size cristae disorganization) associated enhanced reactive oxygen species production. also elicit basal failure illustrated by conversion LC3, LC3-I and/or LC3-II, non-degradation SQSTM1/p62, inconsistent Parkin PINK1 recruitment mitochondria, levels membrane matrix proteins, deficient fusion mitochondria lysosomes. We confirm morphological impaired vivo young 3xTgAD transgenic mice treated inhibitor as well adeno-associated-virus-C99 injected mice. Comparison aged 2xTgAD indicates that, besides APP-CTFs, additional late-stage activation occurs. Importantly, report on human post-mortem sporadic brains correlating molecular signature. Since defective plays a pivotal role pathogenesis, targeting dysfunctions counteracting may represent relevant therapeutic interventions AD.

Язык: Английский

Процитировано

195
Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls DOI Creative Commons
Swagata Ghatak,

Nima Dolatabadi,

Dorit Trudler

и другие.

eLife, Год журнала: 2019, Номер 8

Опубликована: Ноя. 29, 2019

Human Alzheimer’s disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, underlying mechanism for this excessive excitability remains incompletely understood. To investigate basis hyperactivity, we performed electrophysiological immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In neurons/organoids, found increased excitatory bursting activity, which could be explained part a decrease neurite length. neurons also displayed sodium current density decreased inhibitory activity. Our findings establish as relevant model early pathophysiology provide mechanistic insight into observed

Язык: Английский

Процитировано

190
A new era in functional genomics screens DOI
Laralynne Przybyla, Luke A. Gilbert

Nature Reviews Genetics, Год журнала: 2021, Номер 23(2), С. 89 - 103

Опубликована: Сен. 20, 2021

Язык: Английский

Процитировано

189
A reference human induced pluripotent stem cell line for large-scale collaborative studies DOI Creative Commons
Caroline B. Pantazis, Andrian Yang,

Erika Lara

и другие.

Cell stem cell, Год журнала: 2022, Номер 29(12), С. 1685 - 1702.e22

Опубликована: Дек. 1, 2022

Human induced pluripotent stem cell (iPSC) lines are a powerful tool for studying development and disease, but the considerable phenotypic variation between makes it challenging to replicate key findings integrate data across research groups. To address this issue, we sub-cloned candidate human iPSC deeply characterized their genetic properties using whole genome sequencing, genomic stability upon CRISPR-Cas9-based gene editing, including differentiation commonly used types. These studies identified KOLF2.1J as an all-around well-performing line. We then shared with groups around world who tested its performance in head-to-head comparisons own preferred diverse range of protocols functional assays. On strength these findings, have made gene-edited derivative clones readily accessible promote standardization required large-scale collaborative science field.

Язык: Английский

Процитировано

145
Mitophagy in Alzheimer’s disease: Molecular defects and therapeutic approaches DOI Creative Commons
Arnaud Mary, Fanny Eysert, Frédéric Checler

и другие.

Molecular Psychiatry, Год журнала: 2022, Номер 28(1), С. 202 - 216

Опубликована: Июнь 3, 2022

Abstract Mitochondrial dysfunctions are central players in Alzheimer’s disease (AD). In addition, impairments mitophagy, the process of selective mitochondrial degradation by autophagy leading to a gradual accumulation defective mitochondria, have also been reported occur AD. We provide an updated overview recent discoveries and advancements on mitophagic molecular AD-derived fluids cells as well AD brains. discuss studies using cellular animal models that unraveled contribution relevant AD-related proteins (Tau, Aβ, APP-derived fragments APOE) mitophagy failure. accordance with important role impaired AD, we report various therapeutic strategies aiming at stimulating summarize benefits these potential human clinical trials.

Язык: Английский

Процитировано

137
Recent Advances in the Modeling of Alzheimer’s Disease DOI Creative Commons
Hiroki Sasaguri, Shoko Hashimoto, Naoto Watamura

и другие.

Frontiers in Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Март 31, 2022

Since 1995, more than 100 transgenic (Tg) mouse models of Alzheimer's disease (AD) have been generated in which mutant amyloid precursor protein (APP) or APP/presenilin 1 (PS1) cDNA is overexpressed (

Язык: Английский

Процитировано

118
Answer ALS, a large-scale resource for sporadic and familial ALS combining clinical and multi-omics data from induced pluripotent cell lines DOI Creative Commons
Emily G. Baxi, Terri G. Thompson, Jonathan Li

и другие.

Nature Neuroscience, Год журнала: 2022, Номер 25(2), С. 226 - 237

Опубликована: Фев. 1, 2022

Answer ALS is a biological and clinical resource of patient-derived, induced pluripotent stem (iPS) cell lines, multi-omic data derived from iPS neurons longitudinal smartphone over 1,000 patients with ALS. This provides population-level that may be employed to identify clinical-molecular-biochemical subtypes amyotrophic lateral sclerosis (ALS). A unique smartphone-based system was collect deep data, including fine motor activity, speech, breathing linguistics/cognition. The spinal were blood each patient these cells underwent analytics whole-genome sequencing, RNA transcriptomics, ATAC-sequencing proteomics. intent for the generation integrated signatures using bioinformatics, statistics computational biology establish patterns lead better understanding underlying mechanisms disease, subgroup identification. web portal open-source sharing all developed widespread community-based analytics.

Язык: Английский

Процитировано

112