Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice

Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2

Engaging community pharmacists in the primary prevention of cardiovascular disease: protocol for the Pharmacist Assessment of Adherence, Risk and Treatment in Cardiovascular Disease (PAART CVD) pilot study

Background: Cardiovascular disease (CVD) is the leading cause of death globally. Community pharmacist intervention studies have demonstrated clinical effectiveness for improving several leading individual CVD risk factors. Primary prevention strategies increasingly emphasise the need for consideration of overall cardiovascular risk and concurrent management of multiple risk factors. It is therefore important to demonstrate the feasibility of multiple risk factor management by community pharmacists to ensure continued currency of their role.Methods/Design: This study will be a longitudinal pre- and post-test pilot study with a single cohort of up to 100 patients in ten pharmacies. Patients aged 50-74 years with no history of heart disease or diabetes, and taking antihypertensive or lipid-lowering medicines, will be approached for participation. Assessment of cardiovascular risk, medicines use and health behaviours will be undertaken by a research assistant at baseline and following the intervention (6 months). Validated interview scales will be used where available. Baseline data will be used by accredited medicines management pharmacists to generate a report for the treating community pharmacist. This report will highlight individual patients&rsquo; overall CVD risk and individual risk factors, as well as identifying modifiablehealth behaviours for risk improvement and suggesting treatment and behavioural goals. The treating community pharmacist will use this information to finalise and implement a treatment plan in conjunction with the patient and their doctor. Community pharmacists will facilitate patient improvements in lifestyle, medicines adherence, and medicines management over the course of five counselling sessions with monthly intervals. The primary outcome will be the change to average overall cardiovascular risk, assessed using the Framingham risk equation.Discussion: This study will assess the feasibility of implementing holistic primary CVD prevention programs into community pharmacy, one of the most accessible health services in most developed countries.<br /

Prader–Willi syndrome and autism spectrum disorders: an evolving story

Prader–Willi syndrome (PWS) is well-known for its genetic and phenotypic complexities. Caused by a lack of paternally derived imprinted material on chromosome 15q11–q13, individuals with PWS have mild to moderate intellectual disabilities, repetitive and compulsive behaviors, skin picking, tantrums, irritability, hyperphagia, and increased risks of obesity. Many individuals also have co-occurring autism spectrum disorders (ASDs), psychosis, and mood disorders. Although the PWS 15q11–q13 region confers risks for autism, relatively few studies have assessed autism symptoms in PWS or directly compared social, behavioral, and cognitive functioning across groups with autism or PWS. This article identifies areas of phenotypic overlap and difference between PWS and ASD in core autism symptoms and in such comorbidities as psychiatric disorders, and dysregulated sleep and eating. Though future studies are needed, PWS provides a promising alternative lens into specific symptoms and comorbidities of autism

Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer's disease (AD), accessible through our web portal, profiling chromatin accessibility and gene expression in the same biological samples and uncovering vast cellular heterogeneity. We identified cell-type-specific, disease-associated candidate cis-regulatory elements and their candidate target genes, including an oligodendrocyte-associated regulatory module containing links to APOE and CLU. We describe cis-regulatory relationships in specific cell types at a subset of AD risk loci defined by genome-wide association studies, demonstrating the utility of this multi-omic single-nucleus approach. Trajectory analysis of glial populations identified disease-relevant transcription factors, such as SREBF1, and their regulatory targets. Finally, we introduce single-nucleus consensus weighted gene coexpression analysis, a coexpression network analysis strategy robust to sparse single-cell data, and perform a systems-level analysis of the AD transcriptome

Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint

The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 μg/m2 dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 μg/m2 of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents