Therapeutic Strategies Targeting Amyloid-β in Alzheimer's Disease.

Abstract:

:Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.

journal_name

Curr Alzheimer Res

authors

Pinheiro L,Faustino C

doi

10.2174/1567205016666190321163438

subject

Has Abstract

pub_date

2019-01-01 00:00:00

pages

418-452

issue

5

eissn

1567-2050

issn

1875-5828

pii

CAR-EPUB-97506

journal_volume

16

pub_type

杂志文章,评审
  • The role of α-synuclein in neurodegenerative diseases: from molecular pathways in disease to therapeutic approaches.

    abstract::Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD). The formation of the cytoplasmic inclusions named "Lewy bodies" in the brain, considered to be a marker for neuronal degeneration in PD and dementia with Lewy bodies. However, Lewy bodies (LBs) are also obser...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/1567205011310060002

    authors: Al-Mansoori KM,Hasan MY,Al-Hayani A,El-Agnaf OM

    更新日期:2013-07-01 00:00:00

  • Pan-amyloid oligomer specific scFv antibody attenuates memory deficits and brain amyloid burden in mice with Alzheimer's disease.

    abstract::Amyloid oligomers have a critical function in the pathologic processes of various amyloidoses, such as Alzheimer's disease (AD), Parkinson disease (PD), Huntington's disease, prion-related diseases, type 2 diabetes, and hereditary renal amyloidosis. Our previous reports demonstrated that a conformation-dependent oligo...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/15672050113106660176

    authors: Zhao M,Wang SW,Wang YJ,Zhang R,Li YN,Su YJ,Zhou WW,Yu XL,Liu RT

    更新日期:2014-01-01 00:00:00

  • Fruitless Wolfberry-Sprout Extract Rescued Cognitive Deficits and Attenuated Neuropathology in Alzheimer's Disease Transgenic Mice.

    abstract:BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative disease featured by memory loss, neuroinflammation and oxidative stress. Overproduction or insufficient clearance of Aβ leads to its pathological aggregation and deposition, which is considered the predominant neuropathological hallmark of AD. Therefore, reduci...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/1567205015666180404160625

    authors: Liu SY,Lu S,Yu XL,Yang SG,Liu W,Liu XM,Wang SW,Zhu J,Ji M,Liu DQ,Zhang ZP,Liu RT

    更新日期:2018-01-01 00:00:00

  • Usefulness of 18F Florbetaben in Diagnosis of Alzheimer's Disease and Other Types of Dementia.

    abstract::In the last decade, several radiolabeled compounds have been developed for the imaging in vivo of amyloid pathology by means of Positron Emission Tomography (PET). Among these, 18F Florbetaben appear to be one of the most reliable for its high affinity for amyloid plaques in brain and its radio-chemical properties tha...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/1567205013666160620114309

    authors: Chiaravalloti A,Danieli R,Lacanfora A,Palumbo B,Caltagirone C,Schillaci O

    更新日期:2017-01-01 00:00:00

  • Isotyping the human TOMM40 variable-length polymorphism by gene amplification and restriction digest.

    abstract::Recent studies have shown that the translocase of outer mitochondrial membrane 40 homolog (TOMM40) contains a polymorphic poly-T variant, the long variant of which is associated with an increase in AD incidence among APOE 3 carriers. Current methods to isotype the poly-T region rely on long PCR, subcloning and sequenc...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/156720512804142921

    authors: Greco SJ,Hamzelou A,Johnston JM,Richardson S,Smith MA,Perry G,Ashford JW,Tezapsidis N

    更新日期:2012-12-01 00:00:00

  • Auto-Contractive Maps: an artificial adaptive system for data mining. An application to Alzheimer disease.

    abstract::This article presents a new paradigm of Artificial Neural Networks (ANNs): the Auto-Contractive Maps (Auto-CM). The Auto-CM differ from the traditional ANNs under many viewpoints: the Auto-CM start their learning task without a random initialization of their weights, they meet their convergence criterion when all thei...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/156720508785908928

    authors: Buscema M,Grossi E,Snowdon D,Antuono P

    更新日期:2008-10-01 00:00:00

  • Autoimmunity in Alzheimer's disease as evidenced by plasma immunoreactivity against RAGE and Abeta42: complication of diabetes.

    abstract::Features of autoimmunity have been associated with both Alzheimer's disease (AD) and with diabetes. In both diseases high levels of advanced glycation end products (AGEs) and their receptor (RAGE) have been detected in tissues and in the circulation. In addition high titers of antibodies directed against a RAGE-like p...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/156720506777632899

    authors: Mruthinti S,Schade RF,Harrell DU,Gulati NK,Swamy-Mruthinti S,Lee GP,Buccafusco JJ

    更新日期:2006-07-01 00:00:00

  • Prevalence of Cognitive Impairment and Dementia in Malays - Epidemiology of Dementia in Singapore Study.

    abstract:OBJECTIVE:To study the prevalence of cognitive impairment and dementia in communitydwelling Malays from Singapore; and to examine differences in prevalence among Chinese and Malays. METHODS:Subjects (≥ 60 years) - drawn from the Malay component of the on-going multiethnic Epidemiology of Dementia in Singapore study - ...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/1567205012666151002123813

    authors: Hilal S,Tan CS,Xin X,Amin SM,Wong TY,Chen C,Venketasubramanian N,Ikram MK

    更新日期:2017-01-01 00:00:00

  • Piper sarmentosum Roxb. Root Extracts Confer Neuroprotection by Attenuating Beta Amyloid-Induced Pro-Inflammatory Cytokines Released from Microglial Cells.

    abstract:BACKGROUND:Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that eventually leads to severe cognitive impairment. Although the exact etiologies of AD still remain elusive, increasing evidence suggests that neuroinflammation cascades mediated by microglial cells are associated with AD. Piper sarme...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/1567205016666190228124630

    authors: Chan EWL,Yeo ETY,Wong KWL,See ML,Wong KY,Gan SY

    更新日期:2019-01-01 00:00:00

  • Everyday cognition scale items that best discriminate between and predict progression from clinically normal to mild cognitive impairment.

    abstract:BACKGROUND:Impairment in instrumental activities of daily living (IADL) starts as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer's disease (AD) dementia. However, most IADL scales have not shown IADL alterations in clinically normal (CN) elderly. The objective of this study was to det...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/1567205011666141001120903

    authors: Marshall GA,Zoller AS,Kelly KE,Amariglio RE,Locascio JJ,Johnson KA,Sperling RA,Rentz DM,For The Alzheimer's Disease Neuroimaging Initiative

    更新日期:2014-01-01 00:00:00

  • Alzheimer's and dementia in the oldest-old: a century of challenges.

    abstract::Alzheimer's disease (AD) is the most common type of dementia in the US and much of the world with rates increasing exponentially from age 65. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the c...

    journal_title:Current Alzheimer research

    pub_type: 历史文章,杂志文章,评审

    doi:10.2174/156720506779025233

    authors: Kawas CH,Corrada MM

    更新日期:2006-12-01 00:00:00

  • Acetylcholinesterase Inhibitor Donepezil Effects on Plasma β-Hydroxybutyrate Levels in the Treatment of Alzheimer's Disease.

    abstract:BACKGROUND:Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesterase inhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesterase inhibitory ...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/1567205015666180601091818

    authors: Wan L,Lu J,Fu J,Huang J,Yang Q,Xin B,Chen L,Huo Y,Zhong Y,Guo C

    更新日期:2018-01-01 00:00:00

  • Lipid alterations in the earliest clinically recognizable stage of Alzheimer's disease: implication of the role of lipids in the pathogenesis of Alzheimer's disease.

    abstract::Lipids have many important yet distinct functions in cellular homeostasis such as forming an impermeable barrier separating intracellular and extracellular compartments, providing a matrix for the appropriate interactions of membrane-associated proteins, and serving as storage reservoirs for biologically active second...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/1567205052772786

    authors: Han X

    更新日期:2005-01-01 00:00:00

  • Epidemiology and etiology of Alzheimer's disease: from genetic to non-genetic factors.

    abstract::At present, the etiology of Alzheimer's disease (AD) is still unclear, but both genetic and non-genetic factors are thought to take part in the etiopathogenesis of AD. Epidemiologic researches revealed that genetic factors played a decisive role in the development of both early-onset AD (EOAD) and late-onset AD (LOAD)...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/15672050113109990155

    authors: Jiang T,Yu JT,Tian Y,Tan L

    更新日期:2013-10-01 00:00:00

  • Protein trafficking and Alzheimer's disease.

    abstract::Mutations in presenilin 1 (PS1) cause early-onset familial Alzheimer;s disease (FAD). Although FAD accounts for less than 5% of all cases of Alzheimer;s disease (AD), extensive analyses of PS1 function have elucidated an important neuronal mechanism underling AD pathogenesis. PS1 is considered to be an essential compo...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/1567205043480528

    authors: Uemura K,Kuzuya A,Shimohama S

    更新日期:2004-02-01 00:00:00

  • Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures.

    abstract::Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder among the elderly. Nmethyl- D-aspartate receptor (NMDAR) overactivation has been implicated in early synaptic dysfunction that precedes late neurodegeneration in AD. Moreover, oligomers of amyloid-beta peptide (Aβ) 1-42 are considered t...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/156720512802455322

    authors: Mota SI,Ferreira IL,Pereira C,Oliveira CR,Rego AC

    更新日期:2012-09-01 00:00:00

  • Evaluating high-dose rivastigmine patch in severe Alzheimer's disease: analyses with concomitant memantine usage as a factor.

    abstract:BACKGROUND:ACTION, a 24-week, prospective, randomized, parallel-group, double-blind study in patients with severe Alzheimer's disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer's Disease Cooperative Study-Activities ...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.2174/1567205011666141218122835

    authors: Grossberg GT,Farlow MR,Meng X,Velting DM

    更新日期:2015-01-01 00:00:00

  • Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease.

    abstract::Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also ...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720501301151207100616

    authors: Potter H,Granic A,Caneus J

    更新日期:2016-01-01 00:00:00

  • Amyloid beta conformation in aqueous environment.

    abstract::Amyloid beta peptide (Abeta), 42-residue peptide and its variations, is known to form amyloid fibrils in Alzheimer's disease. Solid-state NMR study reveals a parallel beta-sheet structure in the Abeta fibrils. The atomic level structure of Abeta in aqueous environment, however, has not been determined, because of its ...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720508786898424

    authors: Takano K

    更新日期:2008-12-01 00:00:00

  • Memory and consciousness in Alzheimer's disease.

    abstract::Human memory can be split into familiarity and recollection processes which contribute to different aspects of memory function. These separate processes result in different experiential states. In this review, we examine how this dominant theoretical framework can explain the subjective experience of people with Alzhe...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720509788486545

    authors: Souchay C,Moulin CJ

    更新日期:2009-06-01 00:00:00

  • Alzheimer's disease and intelligence.

    abstract::A significant body of evidence has accumulated suggesting that individual variation in intellectual ability, whether assessed directly by intelligence tests or indirectly through proxy measures, is related to risk of developing Alzheimer's disease (AD) in later life. Important questions remain unanswered, however, suc...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720511795745276

    authors: Yeo RA,Arden R,Jung RE

    更新日期:2011-06-01 00:00:00

  • Amyloid β oligomers decrease hippocampal spontaneous network activity in an age-dependent manner.

    abstract::Soluble amyloid beta (Abeta) oligomers might trigger early cognitive impairment in Alzheimer's Disease (AD) through the impairment of proper neuronal network function. We have recently shown that the short sequence Abeta(25-35) affects the spontaneous activity in hippocampal slices, when was added to the bath, at high...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/156720510791383859

    authors: Balleza-Tapia H,Huanosta-Gutiérrez A,Márquez-Ramos A,Arias N,Peña F

    更新日期:2010-08-01 00:00:00

  • Vicious cycles within the neuropathophysiologic mechanisms of Alzheimer's disease.

    abstract::Rigorous scientific research has identified multiple interactive mechanisms that parallel and are likely causative of the development of Alzheimer's disease (AD). Causative mechanisms include genomics, the creation of amyloid beta (Abeta), factors inhibiting the Abeta removal process, the transformation of Abeta to it...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720506776383068

    authors: Standridge JB

    更新日期:2006-04-01 00:00:00

  • Impact of a Clinical Decision Support Tool on Dementia Diagnostics in Memory Clinics: The PredictND Validation Study.

    abstract:BACKGROUND:Determining the underlying etiology of dementia can be challenging. Computer- based Clinical Decision Support Systems (CDSS) have the potential to provide an objective comparison of data and assist clinicians. OBJECTIVES:To assess the diagnostic impact of a CDSS, the PredictND tool, for differential diagnos...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,多中心研究

    doi:10.2174/1567205016666190103152425

    authors: Bruun M,Frederiksen KS,Rhodius-Meester HFM,Baroni M,Gjerum L,Koikkalainen J,Urhemaa T,Tolonen A,van Gils M,Tong T,Guerrero R,Rueckert D,Dyremose N,Andersen BB,Simonsen AH,Lemstra A,Hallikainen M,Kurl S,Herukka SK,Re

    更新日期:2019-01-01 00:00:00

  • Measuring morphological and cellular changes in Alzheimer's dementia: a review emphasizing stereology.

    abstract::From a clinical as well as a neuropathological point of view Alzheimer's disease (AD) has been the focus of intense research for more than three decades. Most studies to identify morphometric correlates with the declining cognitive function in normal aging and AD have employed semi-quantitative methods to assess neuro...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720505774330528

    authors: Stark AK,Pelvig DP,Jørgensen AM,Andersen BB,Pakkenberg B

    更新日期:2005-10-01 00:00:00

  • A randomized, double-blind, placebo-controlled, 16-week study of the H3 receptor antagonist, GSK239512 as a monotherapy in subjects with mild-to-moderate Alzheimer's disease.

    abstract:INTRODUCTION:Histaminergic H3 receptors may play a role in modulating cholinergic and monoaminergic neurotransmission. This Phase II study evaluated the efficacy and safety of GSK239512, a highly potent, brain penetrant H3 receptor antagonist as monotherapy treatment for subjects with mild-to-moderate probable Alzheime...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.2174/1567205010666131212110148

    authors: Grove RA,Harrington CM,Mahler A,Beresford I,Maruff P,Lowy MT,Nicholls AP,Boardley RL,Berges AC,Nathan PJ,Horrigan JP

    更新日期:2014-01-01 00:00:00

  • Early diagnosis of Alzheimer's disease: is MCI too late?

    abstract::The field of aging and dementia research is advancing rapidly toward the stage of earlier identification of clinical symptoms. Ultimately, clinicians would like to be able to identify individuals who are asymptomatic but at risk for developing dementia. In the interim, the construct of mild cognitive impairment (MCI) ...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720509788929237

    authors: Petersen RC

    更新日期:2009-08-01 00:00:00

  • Quality of education and memory test performance in older men: the New York University Paragraph Recall Test normative data.

    abstract:OBJECTIVES:Memory evaluation is a key component in the accurate diagnosis of cognitive disorders.One memory procedure that has shown promise in discriminating disease-related cognitive decline from normal cognitive aging is the New York University Paragraph Recall Test; however, the effects of education have been unexa...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.2174/15672050113109990140

    authors: Mathews M,Abner E,Caban-Holt A,Dennis BC,Kryscio R,Schmitt F

    更新日期:2013-09-01 00:00:00

  • O-GlcNAc modification and the tauopathies: insights from chemical biology.

    abstract::The aggregation of the microtubule-associated protein tau into paired-helical filaments is the defining characteristic of the tauopathies. It has become apparent that the hyperphosphorylation of tau likely plays a role in the aggregation process and thus strategies to reduce tau phosphorylation are generating wide int...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章,评审

    doi:10.2174/156720509789207967

    authors: Yuzwa SA,Vocadlo DJ

    更新日期:2009-10-01 00:00:00

  • Complement C4A and C4B Gene Copy Number Study in Alzheimer's Disease Patients.

    abstract:BACKGROUND/OBJECTIVES:Increasing evidence suggests the importance of neuroinflammation in the pathogenesis of Alzheimer's disease (AD), which is a complex neurodegenerative disorder. Complement activation occurs in the brain of patients with AD and seems to contribute to an important local inflammatory state. Increased...

    journal_title:Current Alzheimer research

    pub_type: 杂志文章

    doi:10.2174/1567205013666161013091934

    authors: Zorzetto M,Datturi F,Divizia L,Pistono C,Campo I,De Silvestri A,Cuccia M,Ricevuti G

    更新日期:2017-01-01 00:00:00