CSF ATN and α‐synuclein co‐pathology in AD, PD, and DLB.

Background: Co‐pathology between Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) remains poorly understood but is relevant for trial design. We aimed to compare CSF markers of amyloid, tau, and neurodegeneration (ATN) and α‐synuclein between AD, PD, DLB and controls, and investigate the influence of demographical, genetic, and clinical factors on amyloid positivity.

Method: As part of the EPND study, we included 337 individuals with AD, PD, DLB and controls from 6 centers.

Day-to-day spontaneous social behaviours is quantitatively and qualitatively affected in a 16p11.2 deletion mouse model.

Background: Autism spectrum disorders affect more than 1% of the population, impairing social communication and increasing stereotyped behaviours. A micro-deletion of the 16p11.2 BP4-BP5 chromosomic region has been identified in 1% of patients also displaying intellectual disabilities.

Plasma biomarkers for Alzheimer's disease: a field-test in a memory clinic.

Background: The key Alzheimer's disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aβ and p-tau), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers.

Ts66Yah, a mouse model of Down syndrome with improved construct and face validity.

Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21). The understanding of genotype-phenotype relationships, the identification of driver genes and various proofs of concept for therapeutics have benefited from mouse models. The premier model, named Ts(1716)65Dn/J (Ts65Dn), displayed phenotypes related to human DS features.

Comparative multi-tissue profiling reveals extensive tissue-specificity in transcriptome reprogramming during thermal adaptation.

Thermal adaptation is an extensively used intervention for enhancing or suppressing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. While the metabolic consequences of thermal acclimation are not limited to the adipose tissues, the impact on the rest of the tissues in context of their gene expression profile remains unclear.

Cold exposure protects from neuroinflammation through immunologic reprogramming.

Autoimmunity is energetically costly, but the impact of a metabolically active state on immunity and immune-mediated diseases is unclear. Ly6C monocytes are key effectors in CNS autoimmunity with an elusive role in priming naive autoreactive T cells. Here, we provide unbiased analysis of the immune changes in various compartments during cold exposure and show that this energetically costly stimulus markedly ameliorates active experimental autoimmune encephalomyelitis (EAE).

Primary mouse osteoblast and osteoclast culturing and analysis.

Mesenchymal-derived osteoblasts play a key role in bone formation via synthesis and mineralization of the bone and bone remodeling. Osteoclasts are multinucleated cells of hematopoietic origin with a role in bone resorption. Here, we describe a protocol for generating primary cultures of these two cell types from bone tissue including the femur, tibia, and humerus of young mice.

Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models.

Background: Gene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features.

Warmth Prevents Bone Loss Through the Gut Microbiota.

Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects.

Oligogenic Effects of 16p11.2 Copy-Number Variation on Craniofacial Development.

A copy-number variant (CNV) of 16p11.2 encompassing 30 genes is associated with developmental and psychiatric disorders, head size, and body mass. The genetic mechanisms that underlie these associations are not understood.

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy.

The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (, , , and ), thinner ( and ), or absent corpus callosum (), revealing a common role for WDR genes in brain connectivity.

Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.

Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms.

Deletion of the App-Runx1 region in mice models human partial monosomy 21.

Partial monosomy 21 (PM21) is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21). The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects.

IGF2 promotes growth of adrenocortical carcinoma cells, but its overexpression does not modify phenotypic and molecular features of adrenocortical carcinoma.

Insulin-like growth factor 2 (IGF2) overexpression is an important molecular marker of adrenocortical carcinoma (ACC), which is a rare but devastating endocrine cancer. It is not clear whether IGF2 overexpression modifies the biology and growth of this cancer, thus more studies are required before IGF2 can be considered as a major therapeutic target. We compared the phenotypical, clinical, biological, and molecular characteristics of ACC with or without the overexpression of IGF2, to address these issues.

Domains of genome-wide gene expression dysregulation in Down's syndrome.

Trisomy 21 is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in trisomy 21, and to eliminate the noise of genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for trisomy 21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either upregulated or downregulated.

Missense mutation in the second RNA binding domain reveals a role for Prkra (PACT/RAX) during skull development.

Random chemical mutagenesis of the mouse genome can causally connect genes to specific phenotypes. Using this approach, reduced pinna (rep) or microtia, a defect in ear development, was mapped to a small region of mouse chromosome 2. Sequencing of this region established co-segregation of the phenotype (rep) with a mutation in the Prkra gene, which encodes the protein PACT/RAX.