An atomic structure of human γ-secretase

Nature, Год журнала: 2015, Номер 525(7568), С. 212 - 217

Опубликована: Авг. 17, 2015

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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Targeting protein aggregation for the treatment of degenerative diseases

Nature Reviews Drug Discovery, Год журнала: 2015, Номер 14(11), С. 759 - 780

Опубликована: Сен. 4, 2015

Язык: Английский

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The antimicrobial protection hypothesis of Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2018, Номер 14(12), С. 1602 - 1614

Опубликована: Окт. 9, 2018

Abstract Objective We explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide rational framework incorporating recent and seemingly independent findings the antimicrobial role of β‐amyloid emerging experimental, genetic, epidemiological data, suggesting innate immune‐mediated inflammation propagates neurodegeneration. Background pathology is characterized by cerebral deposition amyloid‐β protein (Aβ) as β‐amyloid. Genetic studies have confirmed key Aβ AD, revealing that mutation‐mediated shifts peptides generation lead early onset familial disease. However, appears normal majority patients, who lack mutations. In prevailing models nonfamilial individual genetics age‐associated changes brain milieu promote an intrinsically abnormal propensity self‐association. are increasingly inconsistent with characterization oligomerization nonphysiological exclusively pathological activity. Recent suggest ancient, highly conserved effector molecule immunity. Moreover, appear be important immune pathways mediate pathogen entrapment protect against infection. New inflammation‐mediated neurodegeneration immunity led emergence “Antimicrobial Protection Hypothesis” AD. this model, response genuine, or mistakenly perceived, immunochallenge. first entraps neutralizes invading pathogens fibrillization drives neuroinflammatory help fight infection clear β‐amyloid/pathogen deposits. chronic activation pathway leads sustained Mounting data link elevated microbe levels The Antimicrobial Hypothesis reveals how increased microbial burden may directly exacerbate deposition, inflammation, progression. Amyloid cascade hypothesis protection modality Aβ's pathophysiology shifted from stochastic behavior toward dysregulated response. still Thus, extends but remains broadly consistent Cascade overwhelming showing primacy pathology.

Язык: Английский

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The amyloid cascade hypothesis: are we poised for success or failure?

Journal of Neurochemistry, Год журнала: 2016, Номер 139(S2), С. 237 - 252

Опубликована: Июнь 3, 2016

Abstract The first description of Alzheimer's disease ( AD ) was made in 1907 by Alois Alzheimer Allgemeine Zeitschrift fur Psyciatrie und Psychisch‐Gerichtliche Medizin 64, 3, 1907), although other contemporary physicians had similar, and rather more complete, assessments the neuropathological changes present brain (Fischer, Monatsschr Psychiat Neurol 22, 17, 1907). Our knowledge has increased dramatically continues to accelerate. This year is 25 years after publication a series papers that, various ways, articulated amyloid cascade hypothesis ACH for (Beyreuther Masters, Brain Pathol 1, 241–251, 1991; Hardy Allsop, Trends Pharmacol Sci 12, 383–388, Selkoe, Neuron 6, 487–498, Higgins, Science 256, 184–185, 1992). review will cover some familiar territory, but we shall also place into wider context, compare it with hypotheses , explore evolution encompass new findings, determine, irrespective merits itself, whether been useful research field, both academia industry. Finally, how led number therapeutic approaches, all which have, date, failed reach their primary efficacy end‐points clinical trials reflect upon what future may hold. image We (ACH) that have posited explain initiation progression disease. document data support ACH, its deficiencies. list recent failures amyloidocentric drugs anticipate results approaches deliver. article part 60th Anniversary special issue .

Язык: Английский

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Cryo-EM: A Unique Tool for the Visualization of Macromolecular Complexity

Molecular Cell, Год журнала: 2015, Номер 58(4), С. 677 - 689

Опубликована: Май 1, 2015

Язык: Английский

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Three-dimensional structure of human γ-secretase

Nature, Год журнала: 2014, Номер 512(7513), С. 166 - 170

Опубликована: Июнь 27, 2014

Язык: Английский

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Il10 Deficiency Rebalances Innate Immunity to Mitigate Alzheimer-Like Pathology

Neuron, Год журнала: 2015, Номер 85(3), С. 534 - 548

Опубликована: Янв. 22, 2015

Язык: Английский

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Photoaffinity Labeling in Target- and Binding-Site Identification

Future Medicinal Chemistry, Год журнала: 2015, Номер 7(2), С. 159 - 183

Опубликована: Фев. 1, 2015

Photoaffinity labeling (PAL) using a chemical probe to covalently bind its target in response activation by light has become frequently used tool drug discovery for identifying new targets and molecular interactions, probing the location structure of binding sites. Methods identify specific proteins hit molecules from phenotypic screens are highly valuable early discovery. In this review, we summarize principles PAL including design experimental techniques vitro live cell investigations. We emphasize need optimize validate probes highlight examples successful application across multiple disease areas.

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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