Familial Dementia With Frontotemporal Features Associated With <scp>M146V</scp> Presenilin‐1 Mutation

Riudavets, Miguel A.; Bartoloni, Leonardo; Troncoso, Juan C.; Pletniková, Olga; George-Hyslop, Peter St; Schultz, Marcelo; Sevlever, Gustavo; Allegri, Ricardo

doi:10.1111/bpa.12051

Cited by 30 publications

(30 citation statements)

References 32 publications

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“…A role in Aβ aggregation and clearance (Corder et al 1993 ) D694N (Iowa) Extensive cerebral amyloid angiopathy; Widespread neurofibrillary tangles; Increased fibrillogenesis of the Aβ peptide (Grabowski et al 2001 ) BIN1 Adaptor protein potentially involved in synaptic vesicle endocytosis (Hu et al 2011 ) V717I (London) Mild amyloid angiopathy; numerous plaques and tangles. Increased Aβ42/Aβ40 ratio; increased Aβ42 (Goate et al 1991 ) CLU Secreted chaperone involved in apoptosis and complement regulation (Harold et al 2009 ) PS1 M146V Increased Aβ42/Aβ40 ratio; increased Aβ42 (Riudavets et al 2013 ) ABCA7 Member of the superfamily of ATP-binding cassette (ABC) transporters, which transport molecules across membranes. Potential role in lipid homeostasis in immune cells (Hollingworth et al 2011 ) M146L (A>C) Increased Aβ42/Aβ40 ratio; increased Aβ42 (Shioi et al 2007 ) CR1 Mediates cellular binding to particles and immune complexes via activated complement (Corneveaux et al 2010 ) L286 V Increased Aβ42/Aβ total ratio (Frommelt et al 1991 ) PICALM Recruits clathrin and adaptor protein complex 2 (AP2) to cell membranes at sites of coated-pit formation and clathrin-vesicle assembly (Harold et al 2009 ) L166P Numerous Aβ-positive neuritic plaques throughout the cerebral cortex; Increased Aβ42/Aβ ratio (Moehlmann et al 2002 ) MS4A6A Likely involved in activation of T cells (Hollingworth et al 2011 ) PS2 N141I Extensive amyloid plaques; Extensive neurofibrillary tangles (typically a Braak score of V or VI); α-synuclein inclusions, especially in the amygdala; Hippocampal sclerosis.…”

Section: Genetic Studies Of Microgliamentioning

confidence: 99%

Innate immunity in Alzheimer’s disease: the relevance of animal models?

2017

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The mouse is one of the organisms most widely used as an animal model in biomedical research, due to the particular ease with which it can be handled and reproduced in laboratory. As a member of the mammalian class, mice share with humans many features regarding metabolic pathways, cell morphology and anatomy. However, important biological differences between mice and humans exist and must be taken into consideration when interpreting research results, to properly translate evidence from experimental studies into information that can be useful for human disease prevention and/or treatment. With respect to Alzheimer’s disease (AD), much of the experimental information currently known about this disease has been gathered from studies using mainly mice as models. Therefore, it is notably important to fully characterise the differences between mice and humans regarding important aspects of the disease. It is now widely known that inflammation plays an important role in the development of AD, a role that is not only a response to the surrounding pathological environment, but rather seems to be strongly implicated in the aetiology of the disease as indicated by the genetic studies. This review highlights relevant differences in inflammation and in microglia, the innate immune cell of the brain, between mice and humans regarding genetics and morphology in normal ageing, and the relationship of microglia with AD-like pathology, the inflammatory profile, and cognition. We conclude that some noteworthy differences exist between mice and humans regarding microglial characteristics, in distribution, gene expression, and states of activation. This may have repercussions in the way that transgenic mice respond to, and influence, the AD-like pathology. However, despite these differences, human and mouse microglia also show similarities in morphology and behaviour, such that the mouse is a suitable model for studying the role of microglia, as long as these differences are taken into consideration when delineating new strategies to approach the study of neurodegenerative diseases.

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Section: Genetic Studies Of Microgliamentioning

confidence: 99%

Innate immunity in Alzheimer’s disease: the relevance of animal models?

2017

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“…These are usually manifested as frontotemporal dementia (FTD) with or without parkinsonism. Rare cases of familial tauopathy with the presence of Pick bodies are linked to mutations in PS-1 , which encodes presenilin 1 and which is usually causative of early onset familial Alzheimer disease (AD) (13–15). …”

Section: Introductionmentioning

confidence: 99%

Familial Behavioral Variant Frontotemporal Dementia Associated With Astrocyte-Predominant Tauopathy

Ferrer

Legati

García-Moncó

et al. 2015

J Neuropathol Exp Neurol

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A familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy is described in 2 sisters born from consanguineous parents. The neuropathological examination revealed massive accumulation of abnormally hyper-phosphorylated, conformational, truncated at aspartic acid 421, ubiquitinated, and nitrated tau at Tyr29 in cortical astrocyte (including their perivascular foot processes) and Bergmann glia. Smaller amounts of abnormal tau were observed in neurons and rarely in oligodendrocytes. There was decreased expression of glial glutamate transporter in the majority of tau-positive astrocytes. Gel electrophoresis of sarkosyl-insoluble fractions showed 2 bands of 64 and 60 kDa and a doublet of 67–70 kDa (which are different from those seen in Alzheimer disease and in typical 4R and 3R tauopathies) together with several bands of lower molecular weight indicative of truncated tau. Analysis of expression of MAPT isoforms further revealed altered splicing and representation of tau isoforms involving exons 2, 3 and 10. Genetic testing revealed no known mutations in PSEN1, PSEN2, APP, MAPT, GRN, FUS, and TARDBP, and no pathological expansion in C9ORF72. However, a novel rare heterozygous sequence variant (p.Q140H) of uncertain significance was identified in FUS in both siblings.

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“…PS1 mutation cases are marked by both clinical and pathological heterogeneity. In G184V PS1 mutation subjects, neuropathological expression was that of Pick disease without AD plaques [121]. There may be a long prodromal phase with subtle deficits in some cognitive domains and not others, and in a pattern and temporal progression not encountered in sporadic AD.…”

Section: Implications Of Familial Ad In the Molecular Pathologymentioning

confidence: 94%

Molecular Pathology of Alzheimer's Disease

Castellani¹,

Perry²

2013

Colloquium Series on Neurobiology of Alzheimers Disease

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This e-book is an original work commissioned for the Colloquium Digital Library of Life Sciences, a curated collection of time-saving pedagogical resources for researchers and students who want to quickly get up to speed in a new area of life science/biomedical research. Each e-book available in Colloquium is an in-depth overview of a fast-moving or fundamental area of research, authored by a prominent contributor to the field. We call these resources 'Lectures' because authors are asked to provide an authoritative, state-of-the-art overview of their area of expertise, in a manner that is accessible to a broad, diverse audience of scientists (similar to a plenary or keynote lecture at a symposium/meeting/colloquium). Readers are invited to keep current with advances in various disciplines, gain insight into fields other than their own, and refresh their understanding of core concepts in cell & molecular biology. This e-book series on Alzheimer's Disease will provide an up-to-date, comprehensive overview of Alzheimer's Disease and dementia from a multidisciplinary perspective, with a focus on disease pathogenesis and translational neurobiology. The major pathogenic proteins will be described and discussed in depth from the perspective of molecular and cell biology, experimental and transgenic modeling, and in-situ phenotypic expression in humans. Added to this will be in depth discussions of all the major pathogenic theories, including the amyloid and tau protein cascades, oxidative stress, involvement of heavy metals, interplay of the endocrine system, issues surrounded cell cycle activation and protein signaling, and important comorbidities that influence human disease such as vascular neurobiology and synucleinopathy. Treatment paradigms and trials as a function of known components of disease pathogenesis will also be described and discussed in requisite detail that reflects the state of the art. As such, the eBook series will provide a "one stop shop" for the aspiring neuroscientist or physician scientist, and will prove an adaptable framework that can be updated going forward, as dictated by new discoveries and the accumulating scientific literature. Published titles(for future titles please see the website, www.morganclaypool.com/page/lifesci) iv ABSTRACT Alzheimer's Disease is characterized pathologically by two principal hallmark lesions, the senile plaque and the neurofibrillary tangle. Since the identification of each over 100 years ago, the major protein components have been elucidated. This has led in turn to the elaboration of metabolic cascades involving amyloid-β production in the case of the senile plaque, and phosphorylated-tau protein in the case of the neurofibrillary tangle. The pathogenesis and histogenesis of each have been the source of extensive investigation and some controversy in recent years, as both cascades have been implicated in the pathogenesis of Alzheimer's Disease, relied upon in the diagnostic criteria for Alzheimer's Disease at autopsy, and targeted for therapeutic interventio...

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Familial Dementia With Frontotemporal Features Associated With M146V Presenilin‐1 Mutation

Cited by 30 publications

References 32 publications

Innate immunity in Alzheimer’s disease: the relevance of animal models?

Innate immunity in Alzheimer’s disease: the relevance of animal models?

Familial Behavioral Variant Frontotemporal Dementia Associated With Astrocyte-Predominant Tauopathy

Molecular Pathology of Alzheimer's Disease

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