MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer’s disease

Neuronal cell loss is a defining feature of Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD

Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease.

Early Alzheimer's disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions

The ETSF : an e-infrastructure to bridge simulation and experiment

The European Theoretical Spectroscopy Facility (ETSF) is a distributed knowledge network that gives researchers access to state-of-the-art computer simulations for electronic excited states in matter. Focusing on the fundamental knowledge of matter at the quantum-mechanical level, ETSF seeks to transfer this understanding to the future design of technologies in multiple areas

Novel Alzheimer risk genes determine the microglia response to amyloid-beta but not to TAU pathology

Polygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology.status: publishe

Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology

International audiencePolygenic risk scores have identified that genetic variants without genome-wide significance still add to the genetic risk of developing Alzheimer's disease (AD). Whether and how subthreshold risk loci translate into relevant disease pathways is unknown. We investigate here the involvement of AD risk variants in the transcriptional responses of two mouse models: APPswe/PS1L166P and Thy-TAU22. A unique gene expression module, highly enriched for AD risk genes, is specifically responsive to Aβ but not TAU pathology. We identify in this module 7 established AD risk genes (APOE, CLU, INPP5D, CD33, PLCG2, SPI1, and FCER1G) and 11 AD GWAS genes below the genome-wide significance threshold (GPC2, TREML2, SYK, GRN, SLC2A5, SAMSN1, PYDC1, HEXB, RRBP1, LYN, and BLNK), that become significantly upregulated when exposed to Aβ. Single microglia sequencing confirms that Aβ, not TAU, pathology induces marked transcriptional changes in microglia, including increased proportions of activated microglia. We conclude that genetic risk of AD functionally translates into different microglia pathway responses to Aβ pathology, placing AD genetic risk downstream of the amyloid pathway but upstream of TAU pathology

Single-Nucleus RNA-Seq Is Not Suitable for Detection of Microglial Activation Genes in Humans

Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-seq is able to detect cellular state in human tissue. Indeed, snRNA-seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimer's disease. Our comparison of microglia from single cells and single nuclei of four human subjects reveals that, although most genes show similar relative abundances in cells and nuclei, a small population of genes (∼1%) is depleted in nuclei compared to whole cells. This population is enriched for genes previously implicated in microglial activation, including APOE, CST3, SPP1, and CD74, comprising 18% of previously identified microglial-disease-associated genes. Given the low sensitivity of snRNA-seq to detect many activation genes, we conclude that snRNA-seq is not suited for detecting cellular activation in microglia in human disease.status: publishe

The major risk factors for Alzheimer's disease: age, sex, and genes modulate the microglia response to Aβ plaques

Sala Frigerio et al. show how microglia respond to amyloid-β, the Alzheimer's disease (AD)-causing factor. Their major response, the ARMs response, is enriched for AD risk genes, is abolished by Apoe deletion, develops faster in female mice, and is also part of normal aging. Thus, major AD risk factors converge on microglia.</p

microRNA-132 regulates gene expression programs involved in microglial homeostasis

microRNA-132 (miR-132), a known neuronal regulator, is one of the most robustly downregulated microRNAs (miRNAs) in the brain of Alzheimer's disease (AD) patients. Increasing miR-132 in AD mouse brain ameliorates amyloid and Tau pathologies, and also restores adult hippocampal neurogenesis and memory deficits. However, the functional pleiotropy of miRNAs requires in-depth analysis of the effects of miR-132 supplementation before it can be moved forward for AD therapy. We employ here miR-132 loss- and gain-of-function approaches using single-cell transcriptomics, proteomics, and in silico AGO-CLIP datasets to identify molecular pathways targeted by miR-132 in mouse hippocampus. We find that miR-132 modulation significantly affects the transition of microglia from a disease-associated to a homeostatic cell state. We confirm the regulatory role of miR-132 in shifting microglial cell states using human microglial cultures derived from induced pluripotent stem cells

The Inherited Cancer Connect (ICCon) mutation-carrier database

The ICCon Partnership was formed in 2013 through the support of a CCNSW STREP grant. A principal goal of this collaboration is to build a national database of individuals with germline mutations causing hereditary cancer syndromes to promote translational research and improve the health of people with a hereditary predisposition to cancer. The ICCon database is currently in development and will comprise of de-identified clinical data that can be extracted for the purposes of linking families across Australia, providing supportive data for health policy applications, responding to feasibility enquiries for clinical trials, or to identify those patients who are eligible to participate in specific trials, or who may benefit from new advances in therapeutic interventions. The ICCon database will include all known carriers of pathogenic mutations in a cancer predisposition gene who have attended a familial cancer clinic (FCC). It will cover the range of hereditary cancer syndromes and include data collected as part of routine clinical care within the FCC. Data that is planned to be stored include mutation type, cancer diagnosis (if appropriate), cancer treatment (if known), family pedigree (de-identified) and cancer risk management information (if known). FCC patients will have the opportunity to provide additional consent for their treatment information to be linked to ICCon through the CART-WHEEL rare cancer registry. In addition to enabling HREC-approved projects and providing data to inform national policy in the hereditary cancer arena, data from the ICCon database will be able to contribute to both clinical and translational research activities. In the translational research arena the ICCon database will be able to contribute data to the international initiatives aiming to amalgamate mutation data, such as BIC (the Breast Cancer Information Core http://research.nhgri.nih.gov/bic/) and InSiGHT (the International Society for Gastrointestinal Hereditary Tumours http://www.insight-group.org/)