The amyloid hypothesis of Alzheimer's disease at 25 years

EMBO Molecular Medicine, Journal Year: 2016, Volume and Issue: 8(6), P. 595 - 608

Published: March 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

Language: Английский

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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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Impact of multiple pathologies on the threshold for clinically overt dementia

Acta Neuropathologica, Journal Year: 2017, Volume and Issue: 134(2), P. 171 - 186

Published: May 9, 2017

Language: Английский

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Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics

Journal of Neurochemistry, Journal Year: 2015, Volume and Issue: 139(S1), P. 179 - 197

Published: Nov. 7, 2015

Abstract Brain iron homeostasis is increasingly recognized as a potential target for the development of drug therapies aging‐related disorders. Dysregulation metabolism associated with cellular damage and oxidative stress reported common event in several neurodegenerative disorders such Alzheimer′s, Parkinson′s, Huntington′s diseases. Indeed, many proteins initially characterized those diseases amyloid‐β protein, α‐synuclein, huntingtin have been linked to neurochemistry. Iron plays crucial role maintaining normal physiological functions brain through its participation mitochondrial respiration, myelin synthesis, neurotransmitter synthesis metabolism. However, excess potent source radical formation because lack body‐wide export system, tight regulation uptake, transport storage fulfilling while keeping level below toxicity threshold. In this review, we discuss current knowledge on explore how alterations affect neuronal function emphasis dysregulation Alzheimer′s Parkinson′s Finally, recent findings implicating diagnostic therapeutic Alzheimer's Parkinson's image fundamental high metabolic energetic requirements brain. has be maintained delicate balance both overload deficiency are detrimental can trigger neurodegeneration. Here, involvement major This article part special issue Parkinson disease .

Language: Английский

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Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2015, Volume and Issue: 1862(5), P. 887 - 900

Published: Dec. 18, 2015

Language: Английский

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The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D

Cell Metabolism, Journal Year: 2017, Volume and Issue: 26(5), P. 719 - 737.e6

Published: Sept. 29, 2017

Elevated reactive oxygen species (ROS) induce the formation of lipids in neurons that are transferred to glia, where they form lipid droplets (LDs). We show glial and neuronal monocarboxylate transporters (MCTs), fatty acid transport proteins (FATPs), apolipoproteins critical for LD formation. MCTs enable glia secrete absorb lactate, which is converted pyruvate acetyl-CoA neurons. Lactate metabolites provide a substrate synthesis acids, processed by FATP apolipoproteins. In presence high ROS, inhibiting lactate transfer or lowering apolipoprotein levels decreases accumulation flies primary mouse glial-neuronal cultures. human APOE can substitute fly APOE4, an Alzheimer's disease susceptibility allele, impaired promotes neurodegeneration, providing insights into mechanisms.

Language: Английский

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A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward

Neuron, Journal Year: 2019, Volume and Issue: 101(5), P. 820 - 838

Published: March 1, 2019

Language: Английский

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Converging pathways in neurodegeneration, from genetics to mechanisms

Nature Neuroscience, Journal Year: 2018, Volume and Issue: 21(10), P. 1300 - 1309

Published: Sept. 19, 2018

Language: Английский

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Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration

Free Radical Biology and Medicine, Journal Year: 2018, Volume and Issue: 133, P. 221 - 233

Published: Sept. 25, 2018

Language: Английский

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ApoE4: an emerging therapeutic target for Alzheimer’s disease

BMC Medicine, Journal Year: 2019, Volume and Issue: 17(1)

Published: March 20, 2019

The growing body of evidence indicating the heterogeneity Alzheimer's disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that development single magic cure suitable for all cases may not be possible. This calls shift in paradigm where targeted treatment is developed specific AD subpopulations share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), most prevalent risk factor AD, expressed more than half patients and thus an important possible therapeutic target. review focuses initially on effects apoE4 as well corresponding cellular animal models suggested molecular mechanisms which mediate them. second part recent apoE4-targeted (from APOE gene to apoE protein its interactors) approaches have been are ready translated human. Further, issue whether due loss protective function gain toxic discussed herein. It both coexist, certain constituents molecule and/or downstream signaling mediating effect, while others associated function. ApoE4 promising target remains understudied. Recent now paving way effective apoE4-directed approaches.

Language: Английский

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