Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

Cold Spring Harbor Perspectives in Medicine, Год журнала: 2012, Номер 2(6), С. a006262 - a006262

Опубликована: Фев. 21, 2012

Colin L. Masters1 and Dennis J. Selkoe2 The Mental Health Research Institute, University of Melbourne, Parkville 3010, Australia Center for Neurologic Diseases, Harvard Medical School Brigham Women's Hospital, Boston, Massachusetts 02115 Correspondence: c.masters{at}unimelb.edu.au

Язык: Английский

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APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

PLoS Medicine, Год журнала: 2017, Номер 14(3), С. e1002270 - e1002270

Опубликована: Март 28, 2017

Background Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting need to colligate from large series. Methods findings We report here novel update (2012–2016) genetic screening AD-EOAD series ascertained across 28 French hospitals 1993 onwards, bringing total number families with n = 170. Families included when at least two first-degree relatives suffered (EOAD) an age onset (AOO) ≤65 y generations. Furthermore, we also screened 129 sporadic cases AOO below 51 (44% males, mean 45 ± 2 y). APP, PSEN1, or PSEN2 53 families. Of screened, 17 carried PSEN1 mutation 1 APP duplication (13%). Parental DNA was available for 10 carriers, allowing us show that had occurred de novo each case. Thirteen (12 PSEN2) either familial previously unreported. carriers cerebrospinal fluid (CSF) biomarkers, 46 (87%) all three CSF biomarkers—total tau (Tau), phospho-tau (P-Tau), amyloid β (Aβ)42—in abnormal ranges. No carrier biomarkers normal One limitation this study is absence functional assessment possibly probably pathogenic variants, which should help their classification. Conclusions Our suggest nonnegligible fraction occurs novo, high importance counseling, as mutational currently performed only. Among 90 distinct found whole sample isolated cases, definite pathogenicity established only 77%, emphasizing pursue effort classify variants.

Язык: Английский

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The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease

Brain, Год журнала: 2015, Номер 138(10), С. 2814 - 2833

Опубликована: Авг. 17, 2015

Abnormal tau lesions (non-argyrophilic pretangle material, argyrophilic neuropil threads, neurofibrillary tangles) in select types of neurons are crucial for the pathogenesis sporadic Alzheimer's disease. Ongoing formation these persists into end-stage disease and is not subject to remission. The early phase a focus increasing interest because only abnormal forms microtubule-associated protein involved at that point and, contrast late-stage when amyloid-β deposition present, this temporally closer prevailing conditions induce pathological process underlying Extracellular aggregated may be produced under by nerve cells contain tau. One potential trigger hyperphosphorylation conformational change presence non-endogenous pathogen. Subsequently, predictable regional distribution pattern develops phylogenetically late-appearing ontogenetically late-maturing connected via their axons. It hoped hypotheses drawn from considerations, as well recent dissemination models, studies variant conformers, imaging will encourage development new preventative disease-modifying strategies.

Язык: Английский

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Presenilins and -Secretase: Structure, Function, and Role in Alzheimer Disease

Cold Spring Harbor Perspectives in Medicine, Год журнала: 2011, Номер 2(1), С. a006304 - a006304

Опубликована: Ноя. 8, 2011

Presenilins were first discovered as sites of missense mutations responsible for early-onset Alzheimer disease (AD). The encoded multipass membrane proteins subsequently found to be the catalytic components γ-secretases, membrane-embedded aspartyl protease complexes generating carboxyl terminus amyloid β-protein (Aβ) from protein precursor (APP). complex also cleaves a variety other type I integral proteins, most notably Notch receptor, signaling which is involved in many cell differentiation events. Although γ-secretase top target developing disease-modifying AD therapeutics, interference with should avoided. Compounds that alter Aβ production by without affecting proteolysis and have been identified are currently at various stages drug development pipeline.

Язык: Английский

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

Science, Год журнала: 2022, Номер 375(6577), С. 167 - 172

Опубликована: Янв. 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

Язык: Английский

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The familial Alzheimer's disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons

Human Molecular Genetics, Год журнала: 2014, Номер 23(13), С. 3523 - 3536

Опубликована: Фев. 12, 2014

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by extracellular plaques containing amyloid β (Aβ)-protein and intracellular tangles hyperphosphorylated Tau protein. Here, we describe the generation of inducible pluripotent stem cell lines from patients harboring London familial AD (fAD) precursor protein (APP) mutation (V717I). We examine AD-relevant phenotypes following directed differentiation to forebrain neuronal fates vulnerable in AD. observe that over time mature fates, APP expression levels Aβ increase dramatically. In both immature APPV717I affects β- γ-secretase cleavage APP. Although lies near site transmembrane domain APP, find β-secretase elevated leading increased APPsβ Aβ. Furthermore, this alters initial γ-secretase, resulting an Aβ42 Aβ38. addition altered processing, total phosphorylated observed neurons with mutation. show treatment Aβ-specific antibodies early culture reverses phenotype levels, implicating production fAD phenotype. These studies use human reveal previously unrecognized effects most common provide model system for testing therapeutic strategies types relevant processes.

Язык: Английский

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Forty Years of Clathrin‐coated Vesicles

Traffic, Год журнала: 2015, Номер 16(12), С. 1210 - 1238

Опубликована: Сен. 25, 2015

The purification of coated vesicles and the discovery clathrin by Barbara Pearse in 1975 was a landmark cell biology. Over past 40 years, work from many labs has uncovered molecular details its associated proteins, including how they assemble into vesicle select cargo. Unexpected connections have been found with signalling, development, neuronal transmission, infection, immunity genetic disorders. But there are still number unanswered questions, clathrin‐mediated trafficking is regulated machinery evolved.

Язык: Английский

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Proteolytic Degradation of Amyloid -Protein

Cold Spring Harbor Perspectives in Medicine, Год журнала: 2012, Номер 2(6), С. a006379 - a006379

Опубликована: Фев. 28, 2012

Takaomi Saido1 and Malcolm A. Leissring2 1Riken Brain Science Institute, Saitamo 351-0198, Japan 2Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida 32224 Correspondence: leissring{at}mayo.edu

Язык: Английский

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Physiological Functions of APP Family Proteins

Cold Spring Harbor Perspectives in Medicine, Год журнала: 2011, Номер 2(2), С. a006288 - a006288

Опубликована: Дек. 6, 2011

Ulrike C. Müller1 and Hui Zheng2 Institute for Pharmacy Molecular Biotechnology, University of Heidelberg, D-69120 Germany Huffington Center on Aging Departments & Human Genetics, Cellular Biology Neuroscience, Baylor College Medicine, Houston, Texas 77030 Correspondence: u.mueller{at}urz.uni-hd.de; huiz{at}bcm.edu

Язык: Английский

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α-synuclein in the pathophysiology of Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2019, Номер 14(1)

Опубликована: Июнь 11, 2019

The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson's (PD), dementia Lewy bodies (DLB) multiple system atrophy (MSA), involved in pathophysiology AD. Lewy-related pathology (LRP), primarily comprised αSyn, present a majority autopsied AD brains, higher levels αSyn cerebrospinal fluid (CSF) patients mild cognitive impairment (MCI) have been linked to decline. Recent studies also suggest asymptomatic accumulation Aβ CSF subjects at risk sporadic individuals carrying autosomal dominant mutations. Experimental has further hyperphosphorylation, but pathological actions APOEε4 allele, latter being major genetic factor for both DLB. In this review, we provide summary current proposing an involvement either as active or passive player pathophysiological ensemble AD, furthermore describe detail knowledge structure inferred function.

Язык: Английский

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