The amyloid hypothesis of Alzheimer's disease at 25 years

EMBO Molecular Medicine, Год журнала: 2016, Номер 8(6), С. 595 - 608

Опубликована: Март 29, 2016

Review29 March 2016Open Access The amyloid hypothesis of Alzheimer's disease at 25 years Dennis J Selkoe Ann Romney Center for Neurologic Diseases, Department Neurology, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA Search more papers by this author John Hardy Corresponding Author Reta Lila Weston Institute Molecular Neuroscience, UCL London, UK Information Selkoe1,‡ 2,‡ 1Ann 2Reta ‡These authors contributed equally to work *Corresponding author. Tel: +44 203 108 7466; E-mail: [email protected] EMBO Mol Med (2016)8:595-608https://doi.org/10.15252/emmm.201606210 See the Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions Figures & Info Abstract Despite continuing debate about β-protein (or Aβ hypothesis, new lines evidence from laboratories clinics worldwide support concept that an imbalance between production clearance Aβ42 related peptides is a very early, often initiating factor (AD). Confirmation presenilin catalytic site γ-secretase has provided linchpin: all dominant mutations causing early-onset AD occur either substrate (amyloid precursor protein, APP) or protease (presenilin) reaction generates Aβ. Duplication wild-type APP gene Down's syndrome leads deposits teens, followed microgliosis, astrocytosis, neurofibrillary tangles typical AD. Apolipoprotein E4, which predisposes > 40% cases, been found impair brain. Soluble oligomers isolated patients' brains can decrease synapse number, inhibit long-term potentiation, enhance synaptic depression rodent hippocampus, injecting them into healthy rats impairs memory. human also induce hyperphosphorylation tau AD-relevant epitopes cause neuritic dystrophy cultured neurons. Crossing with transgenic mice enhances tau-positive neurotoxicity. In humans, studies show low cerebrospinal fluid (CSF) amyloid-PET positivity precede other manifestations many years. Most importantly, recent trials three different antibodies (solanezumab, crenezumab, aducanumab) have suggested slowing cognitive decline post hoc analyses mild subjects. Although factors contribute pathogenesis, dyshomeostasis emerged as most extensively validated compelling therapeutic target. Microgliosis early non-specific proliferation migration microglial cells, macrophage-like cells central nervous system, first response brain damage. Astrocytosis final damage injury astrocytes, type glial cell responsible maintaining extracellular ion neurotransmitter concentrations, modulating function, forming blood–brain barrier. Neurofibrillary accumulation hyperphosphorylated commonly disease, aggregates inside nerve bodies, known dystrophic neurites. Plaque deposition fibrils are deposited outside neurons dense formations, senile plaques plaques. FAD familial caused inherited (typically early-onset) opposition "sporadic" late-onset Introduction Few problems modern biomedicine garnered much scientific interest public concern disease. Virtually unknown general four decades ago, risen prevalence estimated 40 million patients worldwide. true number must be higher, given increasing recognition begins least 2–3 before one forgets name grandchild where parked one's car. Since molecular began earnest 1980s, thousands scientists healthcare professionals delved aspects complex, multifactorial syndrome, hoping help now prevent others developing it future. progressive buildup amyloids diverse protein composition various systemic organs devastating diseases than century, idea put forward George Glenner (Glenner Wong, 1984) particular amyloidogenic accumulating (Aβ) could causative met considerable skepticism over ensuing Precisely why so controversial not clear (Selkoe, 2011), but steady accrual data preclinical clinical increasingly supported it. Aβ) (Beyreuther Masters, 1991; Allsop, Selkoe, Higgins, 1992) become model pathogenesis guiding development potential treatments. We reviewed (Fig 1) dozen ago (Hardy 2002). Space precludes full examination here enormous literature on since review; monograph pathobiology contains details (Selkoe et al, 2012). But context yet emergence apparently positive trial data, critical analysis latest developments laboratory clinic warranted timely. review numerous our prior ever-increasing effort being expended. summarize salient findings undergird (Box 1), we discuss several alternative concepts concerns counterposed (Table 1). Box 1: Evidence supporting key role All undergo surrounding cytopathology regions serving memory cognition. Mutations within immediately flanking region aggressive forms FAD. Humans trisomy 21 (Down's syndrome) harbor 3 copies invariably develop neuropathologically Those who die their early-to-mid teens (from causes) abundant diffuse without dystrophy, tangle formation, accrue gradually such subjects late beyond. Inheritance missense mutation decreases aggregation lifelong protects against age-related decline. Missense 1 2 common AD, subunit γ-secretase. result relative increases Aβ42/43 peptides. These hydrophobic species self-aggregate, leading profound mid-life. ApoE4 carriers were once included This allele was markedly increase risk Aβ, excess downstream neuropathology. (late-onset) density, LTP, intraventricular injection adult rats. Human rat neurons; co-administering fully prevents this. penumbra around Accordingly, centrifugal gradient: less abnormality longer distances plaque edge. Based biomarker studies, CSF scans AD-related changes (increased tau, decreased cerebral glucose metabolism, atrophy, dementia) Trials monoclonal (but moderate) patients. Other proteins proven organ failure, lowering its yields benefits Figure 1. sequence major pathogenic events proposed cascade hypothesisThe curved blue arrow indicates may directly injure synapses neurites neurons, addition activating microglia astrocytes. Download figure PowerPoint Table Findings appear undercut counterarguments explain these discrepancies Counterarguments Amyloid burden correlates well degree impairment do counts widespread event distant dementia lead cellular (e.g., tangles, etc.) proximate neuronal dysfunction Many humans sometimes death noticeably demented Some (not rich abnormal glia); tested rigorously death; oligomer levels per lower (Esparza 2013), suggesting effectively sequester non-diffusible, neurotoxic state, up point neuropathological suggest Such searched systematically soluble genetics proves Aβ-elevating alteration whereas amyloid-related A fundamentally due loss function AD-causing indeed act through partial protease, heterozygous produce clinically detectable Notch phenotypes), organismal normal until symptoms mid-life, heralded elevated Aβ40 ratios. Moreover, 99.9% presenilins Numerous anti-amyloid agents pre-specified endpoints Several had inadequate poor penetration, little change, and/or indexes tramiprosate; R-flurbiprofen; semagacestat). failed enrolled late-mild moderate stages conducted produced suggestive benefit. done obligatory imaging turned out ~25% amyloid-negative (i.e., did AD) New insights homeostasis fact alter proteolytic processing way elevates Aβ43 long (Scheuner 1996; NB: lie self-aggregation resultant peptides, production). mechanistic explanation discovery genes encode active intramembrane-cleaving enzyme (De Strooper 1998; Wolfe 1999). Subsequent begun illuminate how mediates intramembrane proteolysis (Qi-Takahara 2005; Takami 2009; Chavez-Gutierrez 2012; Okochi 2013; Fernandez 2014): initial endopeptidase cleavage near transmembrane/cytoplasmic interface (the ε-cleavage) multiple carboxypeptidase cleavages each sequentially removes 4 C-terminal amino acids approximately turn helix) 2). process two product start Aβ48/49 Aβ49/50 ε-cleavage. precise effects differ somewhat, cases C- N-terminal "processivity" thus (more self-aggregating) elegant provides biochemical earlier showing Aβ42/Aβ40 ratio humans. γ-Secretase reactions presenilin-mutant tissue showed studied carboxypeptidase-like activity, assays few similar processivity might some non-presenilin-mutant (Szaruga 2015). Aβ42, Aβ43, highly self-aggregating, actually anti-amyloidogenic (Kim 2007). 2. Progressive transmembrane domain Presenilin/γ-secretase complex One group emphasized aforementioned mechanism represents neural phenotype independent (Shen Kelleher, 2007; Xia They presenilin-1 generally hardly raise levels, overlook elevation species, (Saito 2011). interpreted perspective, pinpointing aspartyl allows instead speak terms functional shift principal bonds (Kretner 2016). heterozygotes experience no cleavage; rather, they accelerated precedes AD-typical syndrome. 99% (including disease) express presenilin, cannot pathogenesis. original formulation based part chromosome 21, implying individuals Alzheimer neuropathology because too lifelong. supposition substantiated identification segmental microduplications sub-regions 21. Rare translocation involving only distal telomeric features get (Prasher 1998). Conversely, those rare micro-duplicated rest typically mid-50s (Rovelet-Lecrux 2006). conclusively overexpression causes Even remarkable (A673T) second acid results β-secretase (Jonsson benefit compounded, mutant peptide generated altered properties (Benilova 2014; Maloney Zheng A673T even 2012), age 100 (Kero 2013). reduced resulting AD-protective strongly supports hypothesis. Improved modeling systems Concern expressed limitations available models β-amyloid pathogenicity Early mouse (e.g. Games 1995; Hsiao 1996) suffered reliance high transgene expression drive lack death. FAD-mutant MAPT (tau) (tg) succeeded augmenting pathology tangle-like accumulation, involved (Lewis 2001). Recently, gradual developed judicious use selective knockin endogenous 2014). stem cell-derived skin biopsies then absence (Shi Choi Muratore Moore 2015) formation tau. progress means able substantial culture. both models, extensive neurotoxicity dependent (Rapoport 2002; Jin 2011; Roberson Toward complete Year System Achievement Critique References 1995 Pathology Overexpression, al (1995) 2000 Tangle Overexpression: Lewis (2000) 2001 X Overexpression transgenes: artificiality (2001) 2012 derived Diffuse pathology: pre-tangles Not Shi (2012) 2014 Complex genome Artificiality mutations: Saito (2014) gel system Convincing 2015 PSEN (2015) Cell biology importance discovered 1993 (Corder 1993), advent genomewide association and, recently, exome sequencing loci discovered. Whereas recently described usually weaker effect (Lambert 2013) rarer (Guerreiro Jonsson ApoE4, helped delineate additional biological processes Three types especially important: cholesterol/sterol metabolism; inflammation brain's innate immune system; endosomal vesicle recycling (Jones 2010). E components metabolism cholesterol suspected, genetic implication ApoE contrasting loading depletion tg (Refolo 2000, Work expressing alleles shown influence involves differential isoform (Castellano 2011: discussed below). ABCA7 lipid transporter identified locus (Hollingworth loss-of-function threefold (Steinberg microglia, peripheral macrophages, normally promotes efflux lipids apolipoproteins regulates phagocytosis. knockout hAPP doubling insoluble changing processing, like ApoE, However, need pinpointed. Neuropathologists including important For example, observation elements classical complement (McGeer 1989) prescient. last years, variability determinant risk, implicating immunity investigated detail: Complement Receptor (CR1; Lambert 2009), CD33 (Bertram 2008), TREM2, indirectly deposition. Blockade CR1 inhibits activation potentiates phagocytosis (Crehan Inactivation primary uptake (Griciuc TREM2 sustaining (Wang Thus, genetically implicated helping maintain phagocytosing deposits. increased during 2013, Wang 2015; Matarin go load increases, useful (Suárez-Calvet emerging CNS (Forabosco Zhang Type single-transmembrane receptor principally exclusively undergoes ADAM/γ-secretase (Wunderlich Kleinberger 2014), incompletely understood [reviewed (Lue 2015)]. mutation, R47H, same extent does although upregulation subset Guerreiro suggests compromised development. current R47H AD-associated confer microglia. Deleting significantly associated (Ulrich burden, neuroinflammation, loss, spatial deficits (Jiang And transport surface shedding, impaired phagocytic (Kleinberger latter led shed ectodomain mutations. Endosomal set map regulating category includes SORL1, BIN1, PICALM (Rogaeva Zhao SORL1 previously (Andersen 2005), carrying haplotype confirmed (Young Likewise, appears (Kanatsu addition, across barrier: induced pluripotent (iPSC)-derived endothelial exhibited higher enhanced (Zhao summary, linking (previously "sporadic") provide driving avenues intervention, intervening Recent resolve controversies Connecting tangles: temporal canonical lesions Alois noted his 1906 index case debated ever since. An histopathological staging created Braak (1991) widely establish severity scale progression AD-type cytoskeletal changes, is, neurites, unrelated (it include oligomeric Aβ). detection modest amounts change limbic young middle-aged dying imply would necessarily lived longer. Instead, answer Inherited generation) (Lemere 1996a,b; Bateman 2012) tangles/neurites containing filaments clearly contrast, form frontotemporal subsequent deposition, converse demonstrated Laboratory sequence. hTau substantially behavioral offspring when (Roberson Treating culture cortex hyperphosphorylation, ensues if knocked down (Jin Aβ—particularly (Shankar 2008)—can trigger alterations, indicated. seems "permissive", enabling certain consequences (Maruyama How AD: chronically Aß vascular ApoE3 (Rebeck engineered (Holtzman 2000). detailed quantitative study using vivo microdialysis × hApoE crossed production) E3 E2, closely paralleling observed any contributes differentially sol

Язык: Английский

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Ageing as a risk factor for neurodegenerative disease

Nature Reviews Neurology, Год журнала: 2019, Номер 15(10), С. 565 - 581

Опубликована: Сен. 9, 2019

Язык: Английский

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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies

Cell, Год журнала: 2019, Номер 179(2), С. 312 - 339

Опубликована: Сен. 26, 2019

Язык: Английский

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Alzheimer's disease

European Journal of Neurology, Год журнала: 2017, Номер 25(1), С. 59 - 70

Опубликована: Сен. 5, 2017

Alzheimer's disease, the commonest cause of dementia, is a growing global health concern with huge implications for individuals and society. In this review, current understanding epidemiology, genetics, pathology pathogenesis disease outlined, before its clinical presentation treatment strategies are discussed. Finally, review discusses how our enhanced Alzheimer pathogenesis, including recognition protracted preclinical phase, informing new therapeutic aim moving from to prevention.

Язык: Английский

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Oxidative stress and the amyloid beta peptide in Alzheimer’s disease

Redox Biology, Год журнала: 2017, Номер 14, С. 450 - 464

Опубликована: Окт. 19, 2017

Oxidative stress is known to play an important role in the pathogenesis of a number diseases. In particular, it linked etiology Alzheimer's disease (AD), age-related neurodegenerative and most common cause dementia elderly. Histopathological hallmarks AD are intracellular neurofibrillary tangles extracellular formation senile plaques composed amyloid-beta peptide (Aβ) aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, for example can catalyze production Reactive Oxygen Species (ROS) when bound amyloid-β (Aβ). The ROS thus produced, particular hydroxyl radical which reactive one, may contribute oxidative damage on both Aβ itself surrounding molecule (proteins, lipids, …). This review highlights existing link between AD, consequences towards molecules terms damage. addition, implication ions their interaction redox properties leading discussed, vitro vivo oxidation peptide, at molecular level.

Язык: Английский

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Gut microbiome alterations in Alzheimer’s disease

Scientific Reports, Год журнала: 2017, Номер 7(1)

Опубликована: Окт. 13, 2017

Alzheimer's disease (AD) is the most common form of dementia. However, etiopathogenesis this devastating not fully understood. Recent studies in rodents suggest that alterations gut microbiome may contribute to amyloid deposition, yet microbial communities associated with AD have been characterized humans. Towards end, we bacterial taxonomic composition fecal samples from participants and without a diagnosis dementia due AD. Our analyses revealed has decreased diversity compositionally distinct control age- sex-matched individuals. We identified phylum- through genus-wide differences abundance including Firmicutes, increased Bacteroidetes, Bifidobacterium participants. Furthermore, observed correlations between levels differentially abundant genera cerebrospinal fluid (CSF) biomarkers These findings add growing list diseases alterations, as well be target for therapeutic intervention.

Язык: Английский

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How neuroinflammation contributes to neurodegeneration

Science, Год журнала: 2016, Номер 353(6301), С. 777 - 783

Опубликована: Авг. 18, 2016

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis, and frontotemporal lobar dementia are among the most pressing problems of developed societies with aging populations. Neurons carry out essential functions signal transmission network integration in central nervous system main targets neurodegenerative disease. In this Review, I address how neuron's environment also contributes to neurodegeneration. Maintaining an optimal milieu for neuronal function rests supportive cells termed glia blood-brain barrier. Accumulating evidence suggests that neurodegeneration occurs part because is affected during disease a cascade processes collectively neuroinflammation. These observations indicate therapies targeting glial might provide benefit those afflicted by disorders.

Язык: Английский

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Microglia in Alzheimer’s disease

The Journal of Cell Biology, Год журнала: 2017, Номер 217(2), С. 459 - 472

Опубликована: Дек. 1, 2017

Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature Alzheimer’s disease (AD). Human genetics data point to key role for pathogenesis AD. The majority risk genes AD are highly expressed (and many selectively expressed) by brain. There mounting evidence that protect against incidence AD, as impaired microglial activities altered responses β-amyloid associated with increased risk. On other hand, there also abundant activated can be harmful neurons. Microglia mediate synapse loss engulfment synapses, likely via complement-dependent mechanism; they exacerbate tau pathology secrete inflammatory factors injure neurons directly or neurotoxic astrocytes. Gene expression profiles indicate multiple states neurodegenerative settings, which might explain disparate roles development progression pathology.

Язык: Английский

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Amyloid beta: structure, biology and structure-based therapeutic development

Acta Pharmacologica Sinica, Год журнала: 2017, Номер 38(9), С. 1205 - 1235

Опубликована: Июль 17, 2017

Язык: Английский

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Microglia in neurodegeneration

Nature Neuroscience, Год журнала: 2018, Номер 21(10), С. 1359 - 1369

Опубликована: Сен. 19, 2018

Язык: Английский

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