Aβ oligomer and Alzheimer 's disease

LIU Zhian; LIN Yanling; HAN Aidong

doi:10.13471/j.cnki.acta.snus.2021E046

您当前的位置：

首页 >

文章列表页 >

Aβ oligomer and Alzheimer 's disease

Invited review | 更新时间：2023-11-01

- Aβ oligomer and Alzheimer 's disease
- Acta Scientiarum Naturalium Universitatis Sunyatseni Vol. 61, Issue 3, Pages: 1-10(2022)
- 作者机构：
  
  厦门大学生命科学学院，福建厦门 361100
- 作者简介：
- 基金信息：
- DOI：10.13471/j.cnki.acta.snus.2021E046
  CLC： R749.16
- Published：25 May 2022，
  
  Published Online：15 March 2022，
  
  Received：11 November 2021，
  
  Accepted：22 November 2021
扫描看全文
刘志安,林燕玲,韩爱东.Aβ寡聚体与阿尔茨海默病[J].中山大学学报(自然科学版),2022,61(03):1-10.

LIU Zhian,LIN Yanling,HAN Aidong.Aβ oligomer and Alzheimer 's disease[J].Acta Scientiarum Naturalium Universitatis Sunyatseni,2022,61(03):1-10.
刘志安,林燕玲,韩爱东.Aβ寡聚体与阿尔茨海默病[J].中山大学学报(自然科学版),2022,61(03):1-10. DOI： 10.13471/j.cnki.acta.snus.2021E046.

LIU Zhian,LIN Yanling,HAN Aidong.Aβ oligomer and Alzheimer 's disease[J].Acta Scientiarum Naturalium Universitatis Sunyatseni,2022,61(03):1-10. DOI： 10.13471/j.cnki.acta.snus.2021E046.

摘要

阿尔茨海默病（AD， Alzheimer 's disease）是老年人常见的神经退行性疾病（neurodegenerative diseases），也是痴呆症（dementia）最常见的病因。其主要症状是记忆衰退（memory loss）和进行性认知障碍（progressive cognitive impairment）。β-淀粉样蛋白（Aβ， amyloid β）是一种AD发病的关键蛋白。Aβ在各类脑组织中的超常积累以及聚集形成的β-淀粉样斑块导致AD的发生发展，是过去具有巨大影响力的“淀粉样级联假说”（amyloid cascade hypothesis）的核心观点。但最新的证据表明，Aβ寡聚体（AβO， Aβ oligomer）才是真正诱发AD的神经毒素。本文综述了β-淀粉样蛋白研究的最新进展，重点介绍了Aβ的产生和聚集过程和Aβ寡聚体的分类及其神经毒性。最后，本文还介绍了近些年来基于毒性Aβ寡聚体开发治疗AD药物的研究进展。

Abstract

Alzheimer 's disease （AD） is the most common neurodegenerative disease in the elderly， and also the most common cause of dementia. The main symptoms are memory loss and progressive cognitive impairment. Amyloid β （Aβ） is one of the key proteins in the AD pathogenesis. The occurrence and development of AD caused by the accumulation of Aβ and the abnormal accumulation of β-amyloid plaques in various brain tissues was once regarded as the "amyloid cascade hypothesis" for AD pathogenesis. However， more recent evidences suggest that Aβ oligomers are in fact neurotoxins， leading to an "Aβ oligomer hypothesis"， where toxic Aβ oligomers trigger brain damages that causes the AD pathogenesis. Here we review the latest research progresses on β-amyloid protein， focusing on the process of production and aggregation of Aβ， and the classification and neurotoxicity of the Aβ oligomers. We further highlight new AD therapeutic strategies targeting the toxic Aβ oligomers， as exemplified by anti-Aβ monoclonal antibodies approved for clinic usage in recent years.

关键词

阿尔茨海默病APPAβ寡聚体神经毒性aducanumab

Keywords

Alzheimer 's diseaseamyloid precursor proteinAβ oligomerneurotoxicityaducanumab

references

BHATT J， HERRERA A C， AMICO F D， et al. The world Alzheimer report 2019： Attitudes to dementia［EB/OL］. ［2022-01-14］. https：//www.alzint.org/resource/world-Alzheimer-report-2019/https://www.alzint.org/resource/world-Alzheimer-report-2019/.

OLIVEIRA J M， HENRIQUES A G， MARTINS F， et al. Amyloid-β modulates both AβPP and tau phosphorylation［J］. J Alzheimer's Dis， 2015， 45（2）：495-507.

SHIN W S， DI J， CAO Q， et al. Amyloid beta-protein oligomers promote the uptake of tau fibril seeds potentiating intracellular tau aggregation［J］. Alzheimer's Res Ther， 2019， 11（1）：86.

PINHEIRO L， FAUSTINO C. Therapeutic strategies targeting amyloid-β in Alzheimer's disease［J］. Curr Alzheimer Res， 2019， 16（5）：418-452.

YOSHIKAI S， SASAKI H， DOH-URA K， et al. Genomic organization of the human amyloid beta-protein precursor gene［J］. Gene， 1990， 87（2）：257-263.

ROHAN de SILVA H A， JEN A， WICKENDEN C，et al. Cell-specific expression of beta-amyloid precursor protein isoform mRNAs and proteins in neurons and astrocytes［J］. Brain Res Mol Brain Res， 1997， 47（1/2）：147-156.

ZHANG Y W， THOMPSON R， ZHANG H， et al. APP processing in Alzheimer's disease［J］. Mol Brain， 2011， 4：3.

BAUMKÖTTER F， WAGNER K， EGGERT S， et al. Structural aspects and physiological consequences of APP/APLP trans-dimerization［J］. Exp Brain Res， 2012， 217（3/4）：389-395.

SOBA P， EGGERT S， WAGNER K， et al. Homo- and heterodimerization of APP family members promotes intercellular adhesion［J］. EMBO J， 2005， 24（20）：3624-3634.

JIN L W， NINOMIYA H， ROCH J M， et al. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension［J］. J Neurosci， 1994， 14（9）：5461-5470.

SCHETTINI G， GOVONI S， RACCHI M， et al. Phosphorylation of APP-CTF-AICD domains and interaction with adaptor proteins： Signal transduction and/or transcriptional role-relevance for Alzheimer pathology［J］. J Neurochem， 2010， 115（6）：1299-1308.

HAASS C， KAETHER C， THINAKARAN G， et al. Trafficking and proteolytic processing of APP［J］. Cold Spring Harb Perspect Med， 2012， 2（5）：a006270.

SELKOE D J. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease［J］. Trends Cell Biol， 1998， 8（11）：447-453.

SARKAR D， CHAKRABORTY I， CONDORELLI M， et al. Self-assembly and neurotoxicity of β-amyloid （21-40） peptide fragment： The regulatory role of GXXXG motifs［J］. Chem Med Chem， 2020， 15（3）：293-301.

KANATSU K， MOROHASHI Y， SUZUKI M， et al. Decreased calm expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase［J］. Nat Commun， 2014， 5：3386.

YUKSEL M， TACAL O. Trafficking and proteolytic processing of amyloid precursor protein and secretases in Alzheimer's disease development： An up-to-date review［J］. Eur J Pharmacol， 2019， 856：172415.

RAJENDRAN L， HONSHO M， ZAHN T R，et al. Alzheimer's disease beta-amyloid peptides are released in association with exosomes［J］. Proc Natl Acad Sci USA， 2006， 103（30）：11172-11177.

BIBL M, MOLLENHAUER B, ESSELMANN H, et al. CSF amyloid-beta-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia ［J］. Brain, 2006, 129(5):1177-1187.

JAN A， GOKCE O， LUTHI-CARTER R， et al. The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation， fibrillogenesis， and toxicity［J］. J Biol Chem， 2008， 283（42）：28176-28189.

DAR N J， GLAZNER G W. Deciphering the neuroprotective and neurogenic potential of soluble amyloid precursor protein alpha （sAPPα）［J］. Cell Mol Life Sci， 2020， 77（12）：2315-2330.

WILKINS H M， SWERDLOW R H. Amyloid precursor protein processing and bioenergetics［J］. Brain Res Bull， 2017， 133：71-79.

JIANG S， LI Y， ZHANG X， et al. Trafficking regulation of proteins in Alzheimer's disease［J］. Mol Neurodegener， 2014， 9：6.

IANNUZZI C， IRACE G， SIRANGELO I. Differential effects of glycation on protein aggregation and amyloid formation［J］. Front Mol Biosci， 2014， 1：9.

FERNÀNDEZ-BUSQUETS X， PONCE J， BRAVO R， et al. Modulation of amyloid beta peptide（1-42） cytotoxicity and aggregation in vitro by glucose and chondroitin sulfate［J］. Curr Alzheimer Res， 2010， 7（5）：428-438.

HOU L， SHAO H， ZHANG Y， et al. Solution NMR studies of the Abeta（1-40） and Abeta（1-42） peptides establish that the Met35 oxidation state affects the mechanism of amyloid formation［J］. J Am Chem Soc， 2004， 126（7）：1992-2005.

MORO M L， PHILLIPS A S， GAIMSTER K， et al. Pyroglutamate and isoaspartate modified amyloid-beta in ageing and Alzheimer's disease［J］. Acta Neuropathol Commun， 2018， 6（1）：3.

WANG X， ZHOU X， LI G， et al. Modifications and trafficking of APP in the pathogenesis of Alzheimer's disease［J］. Front Mol Neurosci， 2017， 10：294.

MAZANETZ M P， FISCHER P M. Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases［J］. Nat Rev Drug Discov， 2007， 6（6）：464-479.

NILSBERTH C， WESTLIND-DANIELSSON A， ECKMAN C B， et al. The 'Arctic' APP mutation （E693G） causes Alzheimer's disease by enhanced Abeta protofibril formation［J］. Nat Neurosci， 2001， 4（9）：887-893.

HARDY J A， HIGGINS G A. Alzheimer's disease： The amyloid cascade hypothesis［J］. Science， 1992， 256（5054）：184-185.

MASLIAH E， MALLORY M， HANSEN L， et al. Quantitative synaptic alterations in the human neocortex during normal aging［J］. Neurology， 1993， 43（1）：192-197.

DICKSON D W， CRYSTAL H A， BEVONA C， et al. Correlations of synaptic and pathological markers with cognition of the elderly［J］. Neurobiol Aging， 1995， 16（3）：285-304.

HSIA A Y， MASLIAH E， MCCONLOGUE L， et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models［J］. Proc Natl Acad Sci USA， 1999， 96（6）：3228-3233.

MUCKE L， MASLIAH E， YU G Q， et al. High-level neuronal expression of Abeta 1-42 in wild-type human amyloid protein precursor transgenic mice： Synaptotoxicity without plaque formation［J］. J Neurosci， 2000， 20（11）：4050-4058.

WESTERMAN M A， COOPER-BLACKETER D， MARIASH A， et al. The relationship between Abeta and memory in the TG2576 mouse model of Alzheimer's disease［J］. J Neurosci， 2002， 22（5）：1858-1867.

LAMBERT M P， BARLOW A K， CHROMY B A， et al. Diffusible， nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins［J］. Proc Natl Acad Sci USA， 1998， 95（11）：6448-6453.

WALSH D M， KLYUBIN I， FADEEVA J V， et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo［J］. Nature， 2002， 416（6880）：535-539.

LACOR P N， BUNIEL M C， CHANG L， et al. Synaptic targeting by Alzheimer's-related amyloid beta oligomers［J］. J Neurosci， 2004， 24（45）：10191-10200.

XIA W， YANG T， SHANKAR G， et al. A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease［J］. Arch Neurol， 2009， 66（2）：190-199.

RASOOL S， MARTINEZ-CORIA H， WU J W， et al. Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Aβ deposition and tau pathology in 3xTg-AD mice［J］. J Neurochem， 2013， 126（4）：473-482.

KAYED R， HEAD E， THOMPSON J L， et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis［J］. Science， 2003， 300（5618）：486-489.

HARDY J， SELKOE D J. The amyloid hypothesis of Alzheimer's disease： Progress and problems on the road to therapeutics［J］. Science， 2002， 297（5580）：353-356.

SELKOE D J. Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease［J］. J Clin Invest， 2002， 110（10）：1375-1381.

CHROMY B A， NOWAK R J， LAMBERT M P， et al. Self-assembly of Abeta（1-42） into globular neurotoxins［J］. Biochemistry， 2003， 42（44）：12749-12760.

VELASCO P T， HEFFERN M C， SEBOLLELA A， et al. Synapse-binding subpopulations of Aβ oligomers sensitive to peptide assembly blockers and scFv antibodies［J］. ACS Chem Neurosci， 2012， 3（11）：972-981.

REED M N， HOFMEISTER J J， JUNGBAUER L， et al. Cognitive effects of cell-derived and synthetically derived Aβ oligomers［J］. Neurobiol Aging， 2011， 32（10）：1784-1794.

KAYED R， PENSALFINI A， MARGOL L， et al. Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer［J］. J Biol Chem， 2009， 284（7）：4230-4237.

GLABE C G. Structural classification of toxic amyloid oligomers［J］. J Biol Chem， 2008， 283（44）：29639-29643.

LESNÉ S E， SHERMAN M A， GRANT M， et al. Brain amyloid-β oligomers in ageing and Alzheimer's disease［J］. Brain， 2013， 136（Pt 5）：1383-1398.

BRODY D L， JIANG H， WILDBURGER N， et al. Non-canonical soluble amyloid-beta aggregates and plaque buffering： Controversies and future directions for target discovery in Alzheimer's disease［J］.Alzheimer's Res Ther， 2017， 9（1）：62.

BENILOVA I， KARRAN E， DE STROOPER B. The toxic Aβ oligomer and Alzheimer's disease： An emperor in need of clothes［J］. Nat Neurosci， 2012， 15（3）：349-357.

GLABE C G， KAYED R. Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis［J］. Neurology， 2006， 66（Suppl 1）：S74-S78.

SHANKAR G M， LI S， MEHTA T H， et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory［J］. Nat Med， 2008， 14（8）：837-842.

McDONALD J M， SAVVA G M， BRAYNE C， et al. The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia［J］. Brain， 2010， 133（5）：1328-1341.

JIN M， SHEPARDSON N， YANG T， et al. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce tau hyperphosphorylation and neuritic degeneration［J］. Proc Natl Acad Sci U S A， 2011， 108（14）：5819-5824.

LARSON M E， LESNÉ S E. Soluble Aβ oligomer production and toxicity［J］. J Neurochem， 2012， 120（Suppl 1）：125-139.

SHANKAR G M， BLOODGOOD B L， TOWNSEND M， et al. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway［J］. J Neurosci， 2007， 27（11）：2866-2875.

LI S， HONG S， SHEPARDSON N E， et al. Soluble oligomers of amyloid beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake［J］. Neuron， 2009， 62（6）：788-801.

CLEARY J P， WALSH D M， HOFMEISTER J J， et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function［J］. Nat Neurosci， 2005， 8（1）：79-84.

ABDEL-HAFIZ L， MÜLLER-SCHIFFMANN A， KORTH C， et al. Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease［J］. Neurobiol Aging， 2018， 69：1-9.

MÜLLER-SCHIFFMANN A， ANDREYEVA A， HORN A H， et al. Molecular engineering of a secreted， highly homogeneous， and neurotoxic Aβ dimer［J］. ACS Chem Neurosci， 2011， 2（5）：242-248.

O'MALLEY T T， OKTAVIANI N A， ZHANG D， et al. Aβ dimers differ from monomers in structural propensity， aggregation paths and population of synaptotoxic assemblies［J］. Biochem J， 2014， 461（3）：413-426.

LESNÉ S, KOH M T, KOTILINEK L, et al. A specific amyloid-beta protein assembly in the brain impairs memory ［J］. Nature, 2006, 440(7082):352-357.

CHENG I H， SCEARCE-LEVIE K， LEGLEITER J， et al. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models［J］. J Biol Chem， 2007， 282（33）：23818-23828.

MEILANDT W J， CISSE M， HO K， et al. Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice［J］. J Neurosci， 2009， 29（7）：1977-1986.

ODDO S， CACCAMO A， TRAN L， et al. Temporal profile of amyloid-beta （Abeta） oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology［J］. J Biol Chem， 2006， 281（3）：1599-1604.

SHERMAN M A， LESNÉ S E. Detecting Aβ*56 oligomers in brain tissues［J］. Methods Mol Biol， 2011， 670：45-56.

FOWLER S W， CHIANG A C， SAVJANI R R， et al. Genetic modulation of soluble Aβ rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease［J］. J Neurosci， 2014， 34（23）：7871-7885.

LASAGNA-REEVES C A， GLABE C G， KAYED R. Amyloid-β annular protofibrils evade fibrillar fate in Alzheimer disease brain［J］. J Biol Chem， 2011， 286（25）：22122-22130.

LASHUEL H A， JrLANSBURY P T. Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins？［J］. Q Rev Biophys， 2006， 39（2）：167-201.

CHOI H， LEE W， LEE G， et al. The formation mechanism of segmented ring-shaped Aβ oligomers and protofibrils［J］. ACS Chem Neurosci， 2019， 10（8）：3830-3838.

LAFERLA F M， GREEN K N， ODDO S. Intracellular amyloid-beta in Alzheimer 's disease［J］. Nat Rev Neurosci， 2007， 8（7）：499-509.

MROCZKO B， GROBLEWSKA M， LITMAN-ZAWADZKA A， et al. Cellular receptors of amyloid beta oligomers （AβOs） in Alzheimer's disease［J］. Int J Mol Sci， 2018， 19（7）：1884.

NAGELE R G， D'ANDREA M R， ANDERSON W J， et al. Intracellular accumulation of beta-amyloid（1-42） in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease［J］. Neuroscience， 2002， 110（2）：199-211.

FONAR G， POLIS B， SAMS D S， et al. Modified snake alpha-neurotoxin averts beta-amyloid binding to alpha7 nicotinic acetylcholine receptor and reverses cognitive deficits in Alzheimer's disease mice［J］. Mol Neurobiol， 2021， 58（5）：2322-2341.

BUTTERFIELD S M， LASHUEL H A. Amyloidogenic protein-membrane interactions： Mechanistic insight from model systems［J］. Angew Chem Int Ed Engl， 2010， 49（33）：5628-5654.

GUNN A P， WONG B X， JOHANSSEN T， et al. Amyloid-β peptide Aβ3pE-42 induces lipid peroxidation， membrane permeabilization， and calcium influx in neurons［J］. J Biol Chem， 2016， 291（12）：6134-6145.

JANG H， ZHENG J， NUSSINOV R. Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process［J］. Biophys J， 2007， 93（6）：1938-1949.

SEPÚLVEDA F J， FIERRO H， FERNANDEZ E， et al. Nature of the neurotoxic membrane actions of amyloid-β on hippocampal neurons in Alzheimer's disease［J］. Neurobiol Aging， 2014， 35（3）：472-481.

FERNÁNDEZ-MORALES J C， ARRANZ-TAGARRO J A， CALVO-GALLARDO E， et al. Stabilizers of neuronal and mitochondrial calcium cycling as a strategy for developing a medicine for Alzheimer's disease［J］. ACS Chem Neurosci， 2012， 3（11）：873-883.

KIM T， VIDAL G S， DJURISIC M， et al. Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model［J］. Science， 2013， 341（6152）：1399-1404.

DIERING G H， HUGANIR R L. The AMPA receptor code of synaptic plasticity［J］. Neuron， 2018， 100（2）：314-329.

ZHANG Y， KURUP P， XU J， et al. Reduced levels of the tyrosine phosphatase STEP block β amyloid-mediated GluA1/GluA2 receptor internalization［J］. J Neurochem， 2011， 119（3）：664-672.

GUNTUPALLI S， JANG S E， ZHU T， et al. GluA1 subunit ubiquitination mediates amyloid-β-induced loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid （AMPA） receptors ［J］. J Biol Chem， 2017， 292（20）：8186-8194.

LI F， TSIEN J Z. Memory and the NMDA receptors［J］. N Engl J Med， 2009， 361（3）：302-303.

MÜLLER M K， JACOBI E， SAKIMURA K， et al. NMDA receptors mediate synaptic depression， but not spine loss in the dentate gyrus of adult amyloid beta （Aβ） overexpressing mice［J］. Acta Neuropathol Commun， 2018， 6（1）：110.

WEI W， NGUYEN L N， KESSELS H W， et al. Amyloid beta from axons and dendrites reduces local spine number and plasticity［J］. Nat Neurosci， 2010， 13（2）：190-196.

ALBERDI E， SÁNCHEZ-GÓMEZ M V， CAVALIERE F， et al. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors［J］. Cell Calcium， 2010， 47（3）：264-272.

POPUGAEVA E， PCHITSKAYA E， BEZPROZVANNY I. Dysregulation of neuronal calcium homeostasis in Alzheimer's disease — a therapeutic opportunity？［J］. Biochem Biophys Res Commun， 2017， 483（4）：998-1004.

de FELICE F G， VELASCO P T， LAMBERT M P， et al. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine［J］. J Biol Chem， 2007， 282（15）：11590-11601.

VINCENT B， SUNYACH C， ORZECHOWSKI H D， et al.P53-dependent transcriptional control of cellular prion by presenilins［J］. J Neurosci， 2009， 29（20）：6752-6760.

FLUHARTY B R， BIASINI E， STRAVALACI M， et al. An N-terminal fragment of the prion protein binds to amyloid-beta oligomers and inhibits their neurotoxicity in vivo［J］. J Biol Chem， 2013， 288（11）：7857-7866.

LAURÉN J， GIMBEL D A， NYGAARD H B， et al. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers［J］. Nature， 2009， 457（7233）：1128-1132.

TAKAHASHI R H， TOBIUME M， SATO Y， et al. Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer's disease brain［J］. Neuropathology， 2011， 31（3）：208-214.

TAKAHASHI R H， YOKOTSUKA M， TOBIUME M， et al. Accumulation of cellular prion protein within beta-amyloid oligomer plaques in aged human brains［J］. Brain Pathol， 2021， 31（5）：e12941.

EZPELETA J， BAUDOUIN V， ARELLANO-ANAYA Z E， et al. Production of seedable amyloid-beta peptides in model of prion diseases upon PrPSC-induced PDK1 overactivation［J］. Nat Commun， 2019， 10（1）：3442.

UM J W， KAUFMAN A C， KOSTYLEV M， et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein［J］. Neuron， 2013， 79（5）：887-902.

LOPEZ LOPEZ C， TARIOT P N， CAPUTO A， et al. The Alzheimer's prevention initiative generation program： Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease［J］. Alzheimer's Dement （NY）， 2019， 5：216-227.

GRATTON R， TRICARICO P M， MOLTRASIO C， et al. Pleiotropic role of notch signaling in human skin diseases［J］. Int J Mol Sci， 2020， 21（12）：4214.

FENILI D， BROWN M， RAPPAPORT R， et al. Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology［J］. J Mol Med （Berl）， 2007， 85（6）：603-611.

SALLOWAY S， SPERLING R， KEREN R， et al. A phase 2 randomized trial of ELND005， scyllo-inositol， in mild to moderate Alzheimer disease［J］. Neurology， 2011， 77（13）：1253-1262.

SANTA-MARIA I， HERNANDEZ F， del RIO J， et al. Tramiprosate， a drug of potential interest for the treatment of Alzheimer's disease， promotes an abnormal aggregation of tau［J］. Mol Neurodegener， 2007， 2：17.

KOCIS P， TOLAR M， YU J， et al. Elucidating the Aβ42 anti-aggregation mechanism of action of tramiprosate in Alzheimer's disease： Integrating molecular analytical methods， pharmacokinetic and clinical data［J］. CNS Drugs， 2017， 31（6）：495-509.

AISEN P S， GAUTHIER S， FERRIS S H， et al. Tramiprosate in mild-to-moderate Alzheimer's disease— a randomized， double-blind， placebo-controlled， multi-centre study （the alphase study）［J］. Arch Med Sci， 2011， 7（1）：102-111.

MANZANO S， AGUERA L， AGUILAR M， et al. A review on tramiprosate （homotaurine） in Alzheimer's disease and other neurocognitive disorders［J］. Front Neurol， 2020， 11：614.

JIANG Y， JIANG X， SHI X， et al. Alpha-helical motif as inhibitors of toxic amyloid-beta oligomer generation via highly specific recognition of amyloid surface［J］. Science， 2019， 17：87-100.

MUTTENTHALER M， KING G F， ADAMS D J， et al. Trends in peptide drug discovery［J］. Nat Rev Drug Discov， 2021， 20（4）：309-325.

CUMMINGS J L， TONG G， BALLARD C. Treatment combinations for Alzheimer's disease：Current and future pharmacotherapy options［J］. J Alzheimer's Dis， 2019， 67（3）：779-794.

FOROUTAN N， HOPKINS R B， TARRIDE J E， et al. Safety and efficacy of active and passive immunotherapy in mild-to-moderate Alzheimer's disease： A systematic review and network meta-analysis［J］. Clin Invest Med， 2019， 42（1）：e53-e65.

LOUREIRO J C， PAIS M V， STELLA F， et al. Passive antiamyloid immunotherapy for Alzheimer's disease［J］. Curr Opin Psychiatry， 2020， 33（3）：284-291.

DHILLON S. Aducanumab： First approval［J］. Drugs， 2021， 81（12）：1437-1443.

SEVIGNY J， CHIAO P， BUSSIERE T， et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease［J］. Nature， 2016， 537（7618）：50-56.

TAMPI R R， FORESTER B P， AGRONIN M.Aducanumab： Evidence from clinical trial data and controversies［J/OL］.Drugs Context， 2021.DOI：10.7573/dic.2021-7-3http://dx.doi.org/10.7573/dic.2021-7-3.

KNOPMAN D S， JONES D T， GREICIUS M D. Failure to demonstrate efficacy of aducanumab： An analysis of the emerge and engage trials as reported by Biogen， December 2019［J］. Alzheimer's Dement， 2021， 17（4）：696-701.

SELKOE D J. Alzheimer disease and aducanumab： Adjusting our approach［J］.Nat Rev Neurol，2019，15（7）：365-366.

HUSNA IBRAHIM N， YAHAYA M F， MOHAMED W， et al. Pharmacotherapy of Alzheimer's disease： Seeking clarity in a time of uncertainty［J］. Front Pharmacol， 2020， 11：261.

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

No data

Related Author

Zhian LIU

Yanling LIN

Aidong HAN

Related Institution

No data

Postal code：510275
Tel：020-84112585，84113223 Email：xuebaozr@mail.sysu.edu.cn
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备09064830号-19 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰