Jean-Charles Lambert, France
Institut Pasteur de Lille U1167Author Of 3 Presentations
ALZHEIMER'S GENETIC RISK FACTOR FERMT2 (KINDLIN-2) CONTROLS AXONAL GROWTH AND SYNAPTIC PLASTICITY IN AN APP-DEPENDENT MANNER
Abstract
Aims
Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved.
Methods
We combined genome-wide high-content screenings to identify miRNAs (n = 2,555) and target genes (n = 18,107) involved in the APP metabolism. CRISPR/Cas9 technology has been used to generate cell lines carrying rs7143400 variant located in the FERMT2 3’UTR and its impact on miRNA binding. Involvement of FERMT2 in axonal growth and synaptic connectivity was assessed using primary neurons cultured in microfluidic devices. The functional impact of expression FERMT2 on CA1 basal synaptic transmission and LTP has been recorded in ex vivo mouse hippocampal slices.
Results
Our systematic approaches led us to characterize 180 genes targeted by 41 miRNAs as modulators of APP metabolism. Among these genes, the genetic risk factor of sporadic AD FERMT2, codes for a direct partner of APP. FERMT2 under-expression impacts axonal growth, synaptic connectivity and long-term potentiation in an APP-dependent manner. Lastly, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3’UTR of FERMT2, induced a down-regulation of FERMT2 expression through binding of miR-4504. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls.
Conclusions
Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under-expression in neurons and insight on how this may influence AD pathogenesis.
TOPMED-IMPUTED GENOME-WIDE ASSOCIATION STUDY OF ALZHEIMER’S DISEASE IN THE EADB PROJECT
Abstract
Aims
Strong efforts are still needed to characterize the genetic architecture of Alzheimer’s disease (AD). We thus conducted a complementary genome-wide association study (GWAS) with increased sample size and improved imputation quality of low frequency variants by applying the new TOPMed imputation panel.
Methods
The GWAS was performed in the European Alzheimer Disease Biobank (EADB) dataset. It groups together the main European AD GWAS consortia and a new dataset of 20,464 AD cases and 22,244 controls of European ancestry. Imputation was performed with the TOPMed reference panel or with the Haplotype Reference Consortium panel. The EADB results were meta-analysed with a proxy-AD GWAS performed in the UK Biobank, leading to a total Stage 1 sample size of 39,106 clinically diagnosed AD cases, 46,828 proxy-AD cases and 401,577 controls. The best hits from Stage 1 were finally tested in a large set of independent samples from ADGC and CHARGE.
Results
We identified 65 loci with a genome-wide significant signal of association (P<5x10-8), including 31 new AD loci. The most significant gene sets identified by a pathway analysis relate to amyloid-beta and tau, while many of the other most significant sets relate to lipids and immunity.
Conclusions
The EADB project allowed us to identify several new associated loci for AD, including several candidate genes linked to amyloid precursor protein metabolism or that are likely to be involved in AD-related microglia dysfunctions, and loci already associated with the risk of developing other neurodegenerative diseases. Additional insights into the genetics of AD are expected from other ongoing analyses.
GENE ISOFORM SWITCHING IS A HALLMARK OF ALZHEIMER'S AND OTHER AGING-ASSOCIATED DISEASES
Abstract
Aims
In this work, we aimed at the identification of gene isoform switches in the brain of healthy and Alzheimer’s disease (AD) adult subjects using data from three large studies: Mayo Clinic; Mount Sinai Brain Bank (MSBB) and Religious Orders Study and Memory and Aging Project ROSMAP. We also evaluated isoform switches in two other aging-associated conditions: Progressive supranuclear palsy (PSP) and pathologic aging (PA).
Methods
We used DSeq2 and ISAR to identify gene expression alterations in RNAseq data generated from samples of different brain regions of healthy, AD, PSP and PA subjects. Next, we used scRNAseq to assign altered genes to unique cell types of the adult human brain.
Results
We show that isoform switches are a hallmark of AD, PSP and PA, allowing the identification of gene expression alterations overlooked in classical differential gene expression analyses. Importantly, several gene expression alterations identified by isoform switch analyses are associated with key pathological processes in the brain of AD, PSP and PA subjects. Finally, we also demonstrate a positive correlation between isoform switches and changes in the expression of splicing-associated genes in neuronal cells, suggesting that alternative splicing is altered in the diseased brain.
Conclusions
Our data indicate that isoform switches are an important source of gene expression alteration in the aging brain and might be associated with several biological processes affected in neurodegenerative conditions. Our results also suggest that altered alternative splicing could be a common mechanism in AD and other aging-related diseases.