Mutations of the <i>presenilin I</i> gene in families with early-onset Alzheimer's disease

Campion, Dominique; Flaman, Jean–Michel; Brice, Alexis; Hannequin, Didier; Dubois, Bruno; Martin, Cosette; Moreau, Viviane; Charbonnier, Françoise; Didierjean, Olivier; Tardieu, S; Penet, Christiane; Puel, Michèle; Pasquier, Florence; Doze, F. Le; Bellis, Gil; Calenda, Alphonse; Heilig, Roland; Martínez, María; Mallet, Jacques; Bellis, Michel; Clerget‐Darpoux, Françoise; Agid, Yves; Frébourg, Thierry

doi:10.1093/hmg/4.12.2373

Cited by 260 publications

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“…Among various subtypes of AD, early-onset familial AD is known to be the most aggressive form, striking patients as early as their 20s or 30s (2,3). The clinical symptoms of these patients include accelerated onset of memory loss and dementia and progressive impairment in problem solving, language, and other cognitive abilities.…”

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confidence: 99%

Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2

Feng

Wang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

112

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Early-onset familial Alzheimer's disease is the most aggressive form of Alzheimer's, striking patients as early as their 30s; those patients typically carry mutations in presenilin-1 and presenilin-2. To investigate the coordinated functions of presenilin in the adult brain, we generated double knockout mice, in which both presenilins were deleted in the forebrain. We found that concurrent loss of presenilins in adulthood resulted in massive cortical shrinkage, atrophy of hippocampal molecular layers and corpus callosum, and enlargement of the lateral and third ventricles. We further revealed that deficiency of presenilins caused a series of biochemical alterations, including neuronal atrophy, astrogliosis, caspase-3-mediated apoptosis, and tau hyperphosphorylation. Thus, our study demonstrates that presenilins are essential for the ongoing maintenance of cortical structures and function.A lzheimer's disease (AD) is a degenerative disease of the CNS (1), currently affecting Ͼ25 million people worldwide. Among various subtypes of AD, early-onset familial AD is known to be the most aggressive form, striking patients as early as their 20s or 30s (2, 3). The clinical symptoms of these patients include accelerated onset of memory loss and dementia and progressive impairment in problem solving, language, and other cognitive abilities. In late stages, patients exhibit greatly reduced physical function and are often incontinent, mute, and incapable of caring for themselves. The terminal brains of AD patients are usually hallmarked by accumulations of senile plaques and neurofibrillary tangles, selective shrinkage of cortical and hippocampal tissues, and enlargement of lateral and third ventricle volume (4-6).Discovery of mutations in the presenilin-1 (PS1) and presenilin-2 (PS2) genes in patients with early-onset AD pathogenesis in the mid1990s marked the beginning of the molecular analysis of this devastating subform of the disease (3, 7-10). The PS1 gene encodes a transmembrane protein with ␥-secretase activity important for the proteolytic processing of Notch, amyloid precursor protein, and several other proteins (11,12). In addition, it interacts directly with proteins involved in apoptosis (13,14), tau hyperphosphorylation (15), and neuronal cell adhesion (16). Genetic linkage analysis also revealed a second presenilin gene, PS2, located on chromosome 1 (17, 18). PS1 and PS2 share Ϸ60% homology in amino acid sequence and are expressed ubiquitously in a variety of tissues, including in the brain. In general, PS1 is expressed at a relatively higher level than PS2.Currently, little information is available regarding the functional relationship and in vivo coordination between these two presenilin genes in the adult brain; it is also not clear whether those mutations exert deleterious effects through a gain-offunction or loss-of-function mechanism. Genetic manipulations of Alzheimer's genes represent a valuable approach to the study of the molecular basis underlying the disease process (19-21). Because the conventional...

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confidence: 99%

Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2

Feng

Wang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

112

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“…The first gene mutations related to familial neurodegeneration were identified in AD in the gene encoding amyloid b precursor protein (APP) (51-53), followed by mutations in presenilin 1 (PSEN1) (54,55) and presenilin 2 (PSEN2) (56,57). No mutations directly associated with NFTs have been identified in AD.…”

Section: Geneticsmentioning

confidence: 99%

Mouse Models of Neurodegenerative Diseases: Criteria and General Methodology

Janus

Welzl

2009

Methods in Molecular Biology

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The major symptom of Alzheimer's disease is rapidly progressing dementia, coinciding with the formation of amyloid and tau deposits in the central nervous system, and neuronal death. At present familial cases of dementias provide the most promising foundation for modelling neurodegeneration. We describe the mnemonic and other major behavioral symptoms of tauopathies, briefly outline the genetics underlying familiar cases and discuss the arising implications for modelling the disease in mostly transgenic mouse lines. We then depict to what degree the most recent mouse models replicate pathological and cognitive characteristics observed in patients.There is no universally valid behavioral test battery to evaluate mouse models. The selection of individual tests depends on the behavioral and/or memory system in focus, the type of a model and how well it replicates the pathology of a disease and the amount of control over the genetic background of the mouse model. However it is possible to provide guidelines and criteria for modelling the neurodegeneration, setting up the experiments and choosing relevant tests. One should not adopt a "one (trans)gene, one disease" interpretation, but should try to understand how the mouse genome copes with the protein expression of the transgene in question. Further, it is not possible to recommend some mouse models over others since each model is valuable within its own constraints, and the way experiments are performed often reflects the idiosyncratic reality of specific laboratories. Our purpose is to improve bridging molecular and behavioural approaches in translational research. AbstractThe major symptom of Alzheimer's disease is rapidly progressing dementia, coinciding with the formation of amyloid and tau deposits in the central nervous system, and neuronal death. At present familial cases of dementias provide the most promising foundation for modelling neurodegeneration. We describe the mnemonic and other major behavioral symptoms of tauopathies, briefly outline the genetics underlying familiar cases and discuss the arising implications for modelling the disease in mostly transgenic mouse lines. We then depict to what degree the most recent mouse models replicate pathological and cognitive characteristics observed in patients. There is no universally valid behavioral test battery to evaluate mouse models. The selection of individual tests depends on the behavioral and/or memory system in focus, the type of a model and how well it replicates the pathology of a disease and the amount of control over the genetic background of the mouse model. However it is possible to provide guidelines and criteria for modelling the neurodegeneration, setting up the experiments and choosing relevant tests. One should not adopt a -one (trans)gene, one disease‖ interpretation, but should try to understand how the mouse genome copes with the protein expression of the transgene in question. Further, it is not possible to recommend some mouse models over others since each model is valuab...

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“…The definition of EOAD is disease occurrence before the age of 65 years (Blennow et al, 2006). Missense mutations that alter a single amino acid in one of the three genes encoding the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2), can result in EOAD (Campion et al, 1995;Sherrington et al, 1996;Janssen et al, 2003). Moreover, EOAD is inheritable in an autosomal dominant pattern (Campion et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

Xiang

Lam

Shui

2015

Biological Chemistry

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Lipids serve many distinct functions in cellular homeostasis such as membrane organization, as a platform for membrane function and protein/protein or protein/lipid interaction, energy storage, as well as secondary messengers in signal transduction. Perturbations in lipid homeostasis may result in abnormal cellular function. Alzheimer's disease (AD) is a neurodegenerative disorder in which the brain represents the primary site of pathology. While there is a plethora of previous work pertaining to AD pathogenesis, the precise mechanism of the disease is still not well-understood. Recent waves of technological advances in the realm of lipidomics have enabled scientists to look at AD pathogenesis from a previously unexplored perspective, and studies have revealed extensive lipid aberrations are implicated in the disease pathology. Herein, we review the critical lipids alternations, which affect amyloid plaque and neurofibrillary tangles formation and accumulation, as well as lipid aberrations related to neuronal and synaptic dysfunction in cells and animal models. We also summarize lipid abnormalities observed in the human cerebrospinal fluid (CSF), as well as other circulating fluids including plasma and serum in association with AD, which could serve as candidate biomarkers to diagnose and monitor the disease.

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Mutations of the presenilin I gene in families with early-onset Alzheimer's disease

Cited by 260 publications

References 0 publications

Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2

Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2

Mouse Models of Neurodegenerative Diseases: Criteria and General Methodology

What can lipidomics tell us about the pathogenesis of Alzheimer disease?

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