Early-Onset Familial Alzheimer's Disease (EOFAD)

Wu, Liyong; Rosa‐Neto, Pedro; Hsiung, Ging-Yuek Robin; Sadovnick, A. Dessa; Masellis, Mario; Black, Sandra E.; Jia, Jianping; Gauthier, Serge

doi:10.1017/s0317167100013949

Cited by 179 publications

(143 citation statements)

References 121 publications

(225 reference statements)

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“…Symptoms usually start around the age of 65 years, except in rare patients with early onset (33-60 years) autosomal dominant AD (ADAD) [2,3]. Drugs currently available for AD provide limited short-term treatment of AD symptoms [4].…”

Section: Introductionmentioning

confidence: 99%

O3‐08‐02: Resting‐State Network Dysfunction in Alzheimer's Disease: A Systematic Review And Meta‐Analysis

Badhwar

Tam

Dansereau

et al. 2016

Alzheimer's & Dementia

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Introduction: We performed a systematic review and meta-analysis of the Alzheimer's disease (AD) literature to examine consistency of functional connectivity alterations in AD dementia and mild cognitive impairment, using resting-state functional magnetic resonance imaging. Methods: Studies were screened using a standardized procedure. Multiresolution statistics were performed to assess the spatial consistency of findings across studies. Results: Thirty-four studies were included (1363 participants, average 40 per study). Consistent alterations in connectivity were found in the default mode, salience, and limbic networks in patients with AD dementia, mild cognitive impairment, or in both groups. We also identified a strong tendency in the literature toward specific examination of the default mode network. Discussion: Convergent evidence across the literature supports the use of resting-state connectivity as a biomarker of AD. The locations of consistent alterations suggest that highly connected hub regions in the brain might be an early target of AD.

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Section: Introductionmentioning

confidence: 99%

O3‐08‐02: Resting‐State Network Dysfunction in Alzheimer's Disease: A Systematic Review And Meta‐Analysis

Badhwar

Tam

Dansereau

et al. 2016

Alzheimer's & Dementia

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“…8A), have been identified, leading to an excessive production of Ab peptides and/or to an increased propensity of the mutant peptides to aggregate [148,149]. Nowadays, within the United States, AD is the 6th leading cause of death [150].…”

Section: Ab Peptide and Alzheimer's Diseasementioning

confidence: 99%

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

2015

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Keywords:Variable domain of heavy-chain antibody Inhibition of protein misfolding and aggregation Protein misfolding diseases Amyloidoses V H H Nanobody a b s t r a c tThe deposition of misfolded peptides and proteins in the form of amyloid fibrils is the hallmark of nearly fifty medical disorders, including Alzheimer's disease, Parkinson's disease, prion diseases and type II diabetes. These disorders, referred to as amyloidoses, generally become apparent late in life. Their psycho-sociological and economic incidence in western societies will be therefore considerable in the coming decades due to the ageing of the population. Neither preventing nor curative treatments are available yet. These disorders constitute therefore a medical challenge of great importance. Thus, an extensive research is being carried out to understand, at the molecular level, (i) how amyloidogenic proteins misfold and convert from their soluble form into amyloid fibrils, and (ii) how these aggregates or some of their oligomeric precursor species are toxic. The formation of amyloid fibrils proceeds through a complex nucleation/polymerisation mechanism with the formation of various species, including small oligomers. In this review, we focus on how V H Hs or nanobodies, the antigen-binding domains of camelid heavy-chain antibodies, are being increasingly used to characterise each of the species formed on the pathway of fibril formation in terms of structure, stability, kinetics of formation and toxicity. We first introduce the characteristic features of nanobodies compared to those of conventional antibody fragments. Thereafter, we discuss how nanobodies, due to their unique properties, are used as probes to dissect the molecular mechanisms of misfolding and aggregation of six proteins associated with diseases, i.e. human lysozyme, b2-microglobulin, a-synuclein, prion, polyadenylate binding protein nuclear 1 and amyloid b-peptide. A brief general presentation of each disease and the associated peptide/protein is also provided. In addition, we discuss how nanobodies could be used as early diagnostic tools and as novel strategies to treat diseases associated with protein misfolding and aggregation.© 2015 Elsevier B.V. and Societe Française de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.Abbreviations: Ab, antibody; Ab, amyloid b-peptide; AD, Alzheimer's disease; ANS, anilino naphthalene-sulfonic acid; AP, alkaline phosphatase; APP, amyloid precursor protein; aSyn, a-synuclein; b2m, b2-microglobulin; BBB, bloodebrain barrier; CDR, complementarity determining region; C m , concentration of mid-denaturation; CR, Congo red; CSF, cerebrospinal fluid; DN6b2m, a truncated form of b2m lacking the six N-terminal amino acids; DLS, dynamic light scattering; DRA, dialysis-related amyloidosis; FR, framework; FTIR, Fourier transform infrared spectroscopy; Fv, variable fragment made of the VH and VL domains of conventional antibodies; GFP, green fluorescent protein; HCAb, heavy-chain antibody; H/D, hydrogen/deuterium; HSQC, heteronuclear s...

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“…PSEN2 mutations are less common and 14 specific mutations have been associated with AD [19] . Mutations within the PSEN proteins affect APP synthesis and proteolysis leading to an increase in the ratio of Aβ42 peptide compared to Aβ40, the former a more toxic form of Aβ peptide that is more prone to oligomerisation and fibril formation [19,20] . Drug treatments have focussed on γ-secretase modulators capable of decreasing the ratio of Aβ42 to Aβ40 peptides [21] .…”

Section: Presenilin-1 and -2mentioning

confidence: 99%

Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

Mohamet

Miazga²,

Ward³

2014

WJSC

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Alzheimer's disease (AD) is a progressive neurodegenerative disease in which patients exhibit gradual loss of memory that impairs their ability to learn or carry out daily tasks. Diagnosis of AD is difficult, particularly in early stages of the disease, and largely consists of cognitive assessments, with only one in four patients being correctly diagnosed. Development of novel therapeutics for the treatment of AD has proved to be a lengthy, costly and relatively unproductive process with attrition rates of > 90%. As a result, there are no cures for AD and few treatment options available for patients. Therefore, there is a pressing need for drug discovery platforms that can accurately and reproducibly mimic the AD phenotype and be amenable to high content screening applications. Here, we discuss the use of induced pluripotent stem cells (iPSCs), which can be derived from adult cells, as a method of recapitulation of AD phenotype in vitro . We assess their potential use in high content screening assays and the barriers that exist to realising their full potential in predictive efficacy, toxicology and disease modelling. At present, a number of limitations need to be addressed before the use of iPSC technology can be fully realised in AD therapeutic applications. However, whilst the use of AD-derived iPSCs in drug discovery remains a fledgling field, it is one with immense potential that is likely to reach fruition within the next few years.© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.Key words: Human induced pluripotent stem cells; Alzheimer's disease; Neurodegenerative diseases; Highthroughput screening assays; Cholinergic neurons; Drug discovery; Stratified medicine Core tip: Alzheimer's disease (AD) affects 36 million people worldwide and is set to double by 2030. Progress in understanding AD has been hindered by a lack of suitable in vitro and in vivo models reflected in > 90% drug attrition rates. Induced pluripotent stem cells are an alternative source of neural cells that can be derived from patients' somatic cells and exhibit AD pathophysiological phenotypes. These cells are amenable to HTS formats required for drug discovery applications. Harnessing this combined potential would provide an unprecedented opportunity to significantly reduce timeframes and costs associated with developing novel therapeutics, ultimately improving patient outcomes.Mohamet L, Miazga NJ, Ward CM. Familial Alzheimer's disease modelling using induced pluripotent stem cell technology. World J Stem Cells 2014; 6(2): 239-247 Available from:

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Early-Onset Familial Alzheimer's Disease (EOFAD)

Cited by 179 publications

References 121 publications

O3‐08‐02: Resting‐State Network Dysfunction in Alzheimer's Disease: A Systematic Review And Meta‐Analysis

O3‐08‐02: Resting‐State Network Dysfunction in Alzheimer's Disease: A Systematic Review And Meta‐Analysis

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

Familial Alzheimer’s disease modelling using induced pluripotent stem cell technology

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