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Article ; Online: Step by step: towards a better understanding of the genetic architecture of Alzheimer's disease.

Lambert, Jean-Charles / Ramirez, Alfredo / Grenier-Boley, Benjamin / Bellenguez, Céline

2023 Volume 28, Issue 7, Page(s) 2716–2727

Abstract: Alzheimer's disease (AD) is considered to have a large genetic component. Our knowledge of this component has progressed over the last 10 years, thanks notably to the advent of genome-wide association studies and the establishment of large consortia that ...

Abstract	Alzheimer's disease (AD) is considered to have a large genetic component. Our knowledge of this component has progressed over the last 10 years, thanks notably to the advent of genome-wide association studies and the establishment of large consortia that make it possible to analyze hundreds of thousands of cases and controls. The characterization of dozens of chromosomal regions associated with the risk of developing AD and (in some loci) the causal genes responsible for the observed disease signal has confirmed the involvement of major pathophysiological pathways (such as amyloid precursor protein metabolism) and opened up new perspectives (such as the central role of microglia and inflammation). Furthermore, large-scale sequencing projects are starting to reveal the major impact of rare variants - even in genes like APOE - on the AD risk. This increasingly comprehensive knowledge is now being disseminated through translational research; in particular, the development of genetic risk/polygenic risk scores is helping to identify the subpopulations more at risk or less at risk of developing AD. Although it is difficult to assess the efforts still needed to comprehensively characterize the genetic component of AD, several lines of research can be improved or initiated. Ultimately, genetics (in combination with other biomarkers) might help to redefine the boundaries and relationships between various neurodegenerative diseases.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Genome-Wide Association Study ; Risk Factors ; Biomarkers ; Apolipoproteins E/genetics
Chemical Substances	Biomarkers ; Apolipoproteins E
Language	English
Publishing date	2023-05-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-023-02076-1
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Article ; Online: Analysis of modular gene co-expression networks reveals molecular pathways underlying Alzheimer's disease and progressive supranuclear palsy.

Iohan, Lukas da Cruz Carvalho / Lambert, Jean-Charles / Costa, Marcos R

PloS one

2022 Volume 17, Issue 4, Page(s) e0266405

Abstract: A comprehensive understanding of the pathological mechanisms involved at different stages of neurodegenerative diseases is key for the advance of preventive and disease-modifying treatments. Gene expression alterations in the diseased brain is a ... ...

Abstract	A comprehensive understanding of the pathological mechanisms involved at different stages of neurodegenerative diseases is key for the advance of preventive and disease-modifying treatments. Gene expression alterations in the diseased brain is a potential source of information about biological processes affected by pathology. In this work, we performed a systematic comparison of gene expression alterations in the brains of human patients diagnosed with Alzheimer's disease (AD) or Progressive Supranuclear Palsy (PSP) and animal models of amyloidopathy and tauopathy. Using a systems biology approach to uncover biological processes associated with gene expression alterations, we could pinpoint processes more strongly associated with tauopathy/PSP and amyloidopathy/AD. We show that gene expression alterations related to immune-inflammatory responses preponderate in younger, whereas those associated to synaptic transmission are mainly observed in older AD patients. In PSP, however, changes associated with immune-inflammatory responses and synaptic transmission overlap. These two different patterns observed in AD and PSP brains are fairly recapitulated in animal models of amyloidopathy and tauopathy, respectively. Moreover, in AD, but not PSP or animal models, gene expression alterations related to RNA splicing are highly prevalent, whereas those associated with myelination are enriched both in AD and PSP, but not in animal models. Finally, we identify 12 AD and 4 PSP genetic risk factors in cell-type specific co-expression modules, thus contributing to unveil the possible role of these genes to pathogenesis. Altogether, this work contributes to unravel the potential biological processes affected by amyloid versus tau pathology and how they could contribute to the pathogenesis of AD and PSP.
MeSH term(s)	Aged ; Alzheimer Disease/metabolism ; Brain/metabolism ; Humans ; Supranuclear Palsy, Progressive/metabolism ; Tauopathies/metabolism ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2022-04-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0266405
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Article ; Online: Genetic Predisposition for White Matter Hyperintensities and Risk of Mild Cognitive Impairment and Alzheimer's Disease: Results from the HELIAD Study.

Sampatakakis, Stefanos N / Mourtzi, Niki / Charisis, Sokratis / Mamalaki, Eirini / Ntanasi, Eva / Hatzimanolis, Alexandros / Ramirez, Alfredo / Lambert, Jean-Charles / Yannakoulia, Mary / Kosmidis, Mary H / Dardiotis, Efthimios / Hadjigeorgiou, Georgios / Sakka, Paraskevi / Scarmeas, Nikolaos

Current issues in molecular biology

2024 Volume 46, Issue 1, Page(s) 934–947

Abstract: The present study investigated the association of genetic predisposition for white matter hyperintensities (WMHs) with incident amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD), as well as whether such an association was influenced ... ...

Abstract	The present study investigated the association of genetic predisposition for white matter hyperintensities (WMHs) with incident amnestic mild cognitive impairment (aMCI) or Alzheimer's disease (AD), as well as whether such an association was influenced by age, sex, and cognitive reserve. Overall, 537 individuals without aMCI or dementia at baseline were included. Among them, 62 individuals developed aMCI/AD at follow up. Genetic propensity to WMH was estimated using a polygenic risk score for WMHs (PRS WMH). The association of PRS WMH with aMCI/AD incidence was examined using COX models. A higher PRS WMH was associated with a 47.2% higher aMCI/AD incidence (
Language	English
Publishing date	2024-01-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2000024-8
ISSN	1467-3045 ; 1467-3037
ISSN (online)	1467-3045
ISSN	1467-3037
DOI	10.3390/cimb46010060
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Article ; Online: Genetics of Alzheimer's disease: where we are, and where we are going.

Bellenguez, Céline / Grenier-Boley, Benjamin / Lambert, Jean-Charles

Current opinion in neurobiology

2019 Volume 61, Page(s) 40–48

Abstract: Alzheimer's disease (AD) has a very strong genetic component, whose characterization has become an essential part of efforts to understand the pathophysiological processes of the disease. Thanks to the systematic use of high-throughput approaches over ... ...

Abstract	Alzheimer's disease (AD) has a very strong genetic component, whose characterization has become an essential part of efforts to understand the pathophysiological processes of the disease. Thanks to the systematic use of high-throughput approaches over the last 10 years, more than 40 genes/loci have been linked to the AD risk. Although some of these signals are likely to be false positives, this genetic knowledge has shed new light on the pathogenesis of AD and, in particular, the major role of microglia. However, our knowledge of the genetics of AD is far from complete, and larger and more diverse genetic studies are required. Lastly, post-GWAS analyses will be needed to make sense of this genetic information without focusing too much on what we think we know about the disease.
MeSH term(s)	Alzheimer Disease ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Microglia
Language	English
Publishing date	2019-12-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1078046-4
ISSN	1873-6882 ; 0959-4388
ISSN (online)	1873-6882
ISSN	0959-4388
DOI	10.1016/j.conb.2019.11.024
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Article: Génétique des maladies d'Alzheimer.

Lambert, Jean-Charles

La Revue du praticien

2011 Volume 61, Issue 7, Page(s) 922–923

Title translation	Genetics of Alzheimer's disease.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/physiopathology ; Genetic Predisposition to Disease ; Humans ; Mutation
Language	French
Publishing date	2011-09
Publishing country	France
Document type	Journal Article
ZDB-ID	205365-2
ISSN	2101-017X ; 0035-2640
ISSN (online)	2101-017X
ISSN	0035-2640
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Article: Mieux comprendre la maladie d'Alzheimer.

Lambert, Jean-Charles

Soins. Gerontologie

2010 , Issue 85, Page(s) 40–41

Title translation	Toward a better understanding of Alzheimer's disease.
MeSH term(s)	Aged ; Alzheimer Disease/pathology ; Alzheimer Disease/psychology ; Alzheimer Disease/therapy ; Brain/pathology ; Humans
Language	French
Publishing date	2010-09
Publishing country	France
Document type	Journal Article
ZDB-ID	2246755-5
ISSN	1268-6034
ISSN	1268-6034
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Article: Using High-Throughput Animal or Cell-Based Models to Functionally Characterize GWAS Signals.

Dourlen, Pierre / Chapuis, Julien / Lambert, Jean-Charles

Current genetic medicine reports

2018 Volume 6, Issue 3, Page(s) 107–115

Abstract: Purpose of review: The advent of genome-wide association studies (GWASs) constituted a breakthrough in our understanding of the genetic architecture of multifactorial diseases. For Alzheimer's disease (AD), more than 20 risk loci have been identified. ... ...

Abstract	Purpose of review: The advent of genome-wide association studies (GWASs) constituted a breakthrough in our understanding of the genetic architecture of multifactorial diseases. For Alzheimer's disease (AD), more than 20 risk loci have been identified. However, we are now facing three new challenges: (i) identifying the functional SNP or SNPs in each locus, (ii) identifying the causal gene(s) in each locus, and (iii) understanding these genes' contribution to pathogenesis. Recent findings: To address these issues and thus functionally characterize GWAS signals, a number of high-throughput strategies have been implemented in cell-based and whole-animal models. Here, we review high-throughput screening, high-content screening, and the use of the Summary: We describe how these strategies have been successfully used to functionally characterize the genes in GWAS-defined risk loci. In the future, these strategies should help to translate GWAS data into knowledge and treatments.
Language	English
Publishing date	2018-05-29
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2167-4876
ISSN	2167-4876
DOI	10.1007/s40142-018-0141-1
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Article: Amyloid-Beta Peptides Trigger Premature Functional and Gene Expression Alterations in Human-Induced Neurons.

Melo de Farias, Ana Raquel / Pelletier, Alexandre / Iohan, Lukas Cruz Carvalho / Saha, Orthis / Bonnefond, Amélie / Amouyel, Philippe / Delahaye, Fabien / Lambert, Jean-Charles / Costa, Marcos R

Biomedicines

2023 Volume 11, Issue 9

Abstract: Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade ... ...

Abstract	Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the causative agent of AD pathology, but we still lack comprehensive understanding of the molecular mechanisms connecting Aβ peptides to neuronal dysfunctions in AD. In this work, we investigate the early effects of Aβ peptide accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). We show that hiNs acutely exposed to low concentrations of both cell-secreted Aβ peptides or synthetic Aβ
Language	English
Publishing date	2023-09-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines11092564
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Article ; Online: Modifications of the endosomal compartment in fibroblasts from sporadic Alzheimer's disease patients are associated with cognitive impairment.

Xicota, Laura / Lagarde, Julien / Eysert, Fanny / Grenier-Boley, Benjamin / Rivals, Isabelle / Botté, Alexandra / Forlani, Sylvie / Landron, Sophie / Gautier, Clément / Gabriel, Cecilia / Bottlaender, Michel / Lambert, Jean-Charles / Chami, Mounia / Sarazin, Marie / Potier, Marie-Claude

Translational psychiatry

2023 Volume 13, Issue 1, Page(s) 54

Abstract: Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer's disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against ... ...

Abstract	Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer's disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD. We previously found that PBMCs from AD patients have larger EEA1-positive puncta, correlating with brain amyloid load. Here we analysed the endosomal compartment of fibroblasts from a very well characterised cohort of AD patients (IMABio3) who underwent thorough clinical, imaging and biomarkers assessments. Twenty-one subjects were included (7 AD with mild cognitive impairment (AD-MCI), 7 AD with dementia (AD-D) and 7 controls) who had amyloid-PET at baseline (PiB) and neuropsychological tests at baseline and close to skin biopsy. Fibroblasts isolated from skin biopsies were immunostained with anti-EEA1 antibody and imaged using a spinning disk microscope. Endosomal compartment ultrastructure was also analysed by electron microscopy. All fibroblast lines were genotyped and their AD risk factors identified. Our results show a trend to an increased EEA1-positive puncta volume in fibroblasts from AD-D as compared to controls (p.adj = 0.12) and reveal enhanced endosome area in fibroblasts from AD-MCI and AD-AD versus controls. Larger puncta size correlated with PiB retention in different brain areas and with worse cognitive scores at the time of biopsy as well as faster decline from baseline to the time of biopsy. Finally, we identified three genetic risk factors for AD (ABCA1, COX7C and MYO15A) that were associated with larger EEA1 puncta volume. In conclusion, the endosomal compartment in fibroblasts could be used as cellular peripheral biomarker for both amyloid deposition and cognitive decline in AD patients.
MeSH term(s)	Humans ; Alzheimer Disease ; Amyloid ; Amyloid beta-Peptides ; Cognitive Dysfunction ; Endosomes/pathology ; Fibroblasts ; Leukocytes, Mononuclear ; Positron-Emission Tomography
Chemical Substances	Amyloid ; Amyloid beta-Peptides
Language	English
Publishing date	2023-02-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-023-02355-z
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Article ; Online: High-Content Screening of Synaptic Density Modulators in Primary Neuronal Cultures.

Coulon, Audrey / Siedlecki-Wullich, Dolores / Najdek, Chloé / Gelle, Carla / Ayral, Anne-Marie / Demiautte, Florie / Lambert, Erwan / Vandeputte, Alexandre / Brodin, Priscille / Mendes, Tiago / Lambert, Jean-Charles / Kilinc, Devrim / Dumont, Julie / Chapuis, Julien

Current protocols

2023 Volume 3, Issue 10, Page(s) e904

Abstract: The synapse, which represents the structural and functional basis of neuronal communication, is one of the first elements affected in several neurodegenerative diseases. To better understand the potential role of gene expression in synapse loss, we ... ...

Abstract	The synapse, which represents the structural and functional basis of neuronal communication, is one of the first elements affected in several neurodegenerative diseases. To better understand the potential role of gene expression in synapse loss, we developed an original high-content screening (HCS) model capable of quantitatively assessing the impact of gene silencing on synaptic density. Our approach is based on a model of primary neuronal cultures (PNCs) from the neonatal rat hippocampus, whose mature synapses are visualized by the relative localization of the presynaptic protein Synaptophysin with the postsynaptic protein Homer1. The heterogeneity of PNCs and the small sizes of the synaptic structures pose technical challenges associated with the level of automation necessary for HCS studies. We overcame these technical challenges, automated the processes of image analysis and data analysis, and carried out tests under real-world conditions to demonstrate the robustness of the model developed. In this article, we describe the screening of a custom library of 198 shRNAs in PNCs in the 384-well plate format. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Culture of primary hippocampal rat neurons in 384-well plates Basic Protocol 2: Lentiviral shRNA transduction of primary neuronal culture in 384-well plates Basic Protocol 3: Immunostaining of the neuronal network and synaptic markers in 384-well plates Basic Protocol 4: Image acquisition using a high-throughput reader Basic Protocol 5: Image segmentation and analysis Basic Protocol 6: Synaptic density analysis.
MeSH term(s)	Animals ; Rats ; Automation ; Bone Plates ; Culture ; Data Analysis ; Neurons ; RNA, Small Interfering
Chemical Substances	RNA, Small Interfering
Language	English
Publishing date	2023-10-26
Publishing country	United States
Document type	Journal Article
ISSN	2691-1299
ISSN (online)	2691-1299
DOI	10.1002/cpz1.904
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