Biology subjects

Sims, R.

Publications and source records attributed to Sims, R..

12 recordsLinked to original sources

bioRxiv2026

New Human IPSC Models of Late-onset Alzheimer's Disease Polygenic Risk Identify Multiple Impairments of Microglial Function

Genetic discoveries implicate microglia in late-onset Alzheimers disease (AD). We modelled AD in a powerful study of 51 human induced pluripotent stem cell (iPSC) microglia derived from high-polygenic risk AD or low-risk cognitively well individuals, sampled from a large cohort. We explored mitochondrial function, cytokine secretion, endocytosis, phagocytosis, lipid accumulation, calcium store release, and chemotaxis under basal conditions and immune challenge. High polygenic risk was independently associated with significant functional deficits in iPSC microglia under immune challenge, in mitochondrial ATP production (p=0.005, -13%), and inflammatory cytokine release (IL-6: p=0.018, -42%; TNF p=0.026, -38.5%). Furthermore, a selective deficit in amyloid-{beta} uptake was identified (p=0.00477, -5.9%). Deficits in inflammatory cytokine release were driven by APOE {varepsilon}4. These findings reflect primary changes in AD pathogenesis predating plaque formation and validate a human in vitro platform for late-onset AD to further understand disease mechanisms and screen drug or genetic therapies.

neuroscience↗

bioRxiv2024

Neuronal downregulation of PLCG2 impairs synaptic function and elicits Alzheimer disease hallmarks

We developed a high content screening to investigate how Alzheimer disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Out of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased A{beta} levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a 10-fold increased AD risk. PLCG2 LoF carriers exhibit low mRNA/protein PLCG2/PLC{gamma}2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single nuclei RNAseq analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexin in neurons. In conclusion, PLC{gamma}2 downregulation could increase AD risk by impairing synaptic functions and increasing the A{beta} levels and Tau phosphorylation in neurons.

neuroscience↗

bioRxiv2021

Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults.

Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-{varepsilon}4, a family history of dementia, and central obesity, on CA1, CA2/3, dentate gyrus (DG) and subiculum in 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields (ASHS) and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and FH status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE {varepsilon}4 carriers showed lower size/complexity than non-carriers. Protocol type did not affect this risk pattern. These findings provide novel evidence for interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults. HighlightsO_LIAge-related inverted U-shaped curve of hippocampal myelin/neurite packing C_LIO_LIObesity-related reductions of hippocampal myelin/neurite packing and size/complexity C_LIO_LIAPOE modifies the effects of obesity on hippocampal size/complexity C_LIO_LIAge-related slowing of spatial navigation C_LIO_LINo APOE, family history, or obesity effects on cognition C_LI

neuroscience↗

bioRxiv2020

Monocyte-specific changes in gene expression implicate LACTB2 and PLIN2 in Alzheimer's disease.

More than 50 genetic loci have been identified as being associated with Alzheimers disease (AD) from genome-wide association studies (GWAS) and many of these are involved in immune pathways and lipid metabolism. Therefore, we performed a transcriptome-wide association study (TWAS) of immune-relevant cells, to study the mis-regulation of genes implicated in AD. We used expression and genetic data from naive and induced CD14+ monocytes and two GWAS of AD to study genetically controlled gene expression in monocytes at different stages of differentiation and compared the results with those from TWAS of brain and blood. We identified nine genes with statistically independent TWAS signals, seven are known AD risk genes from GWAS: BIN1, PTK2B, SPI1, MS4A4A, MS4A6E, APOE and PVR and two, LACTB2 and PLIN2/ADRP, are novel candidate genes for AD. Three genes, SPI1, PLIN2 and LACTB2, are TWAS significant specifically in monocytes. LACTB2 is a mitochondrial endoribonuclease and PLIN2/ADRP associates with intracellular neutral lipid storage droplets (LSDs) which have been shown to play a role in the regulation of the immune response. Notably, LACTB2 and PLIN2 were not detected from GWAS alone.

neuroscience↗

bioRxiv2019

Genetic risk of dementia modifies the impact of obesity on limbic white matter and spatial navigation behavior in cognitively healthy adults.

A family history (FH) of dementia, APOE-{varepsilon}4 genotype, and obesity are major risk factors for developing Alzheimers disease but their combined effects on the brain and cognition remain elusive. We tested the hypothesis that these risk factors affect apparent white matter (WM) myelin and cognition including spatial navigation and processing speed in 166 asymptomatic individuals (38-71 years). Microstructure in temporal [fornix, parahippocampal cingulum, uncinate fasciculus], motor and whole-brain WM was assessed with myelin-sensitive indices from quantitative magnetization transfer [macromolecular proton fraction (MPF)] and axon density from diffusion imaging. Individuals with the highest genetic risk (FH+ and APOE-{varepsilon}4) compared to those with FH+ alone showed obesity-related reductions in MPF and axon density in the right parahippocampal cingulum. No effects were present for those without FH. Furthermore, FH modulated obesity-related effects on spatial navigation behaviour. In summary, an individuals genetic dementia risk influenced the impact of obesity on WM myelin and cognition.

neuroscience↗

bioRxiv2019

Molecular Dynamics simulations of Alzheimer's variants, R47H and R62H, in TREM2 provide evidence for structural alterations behind functional changes

There is strong evidence supporting the association between Alzheimers disease (AD) and protein-coding variants, R47H and R62H in TREM2. The TREM2 protein is an immune receptor found in brain microglia. A structural alteration could therefore have a large effect on the protein. Crystallised structures were used as a base for both WT and mutated proteins. These subjected to 300ns of molecular dynamic simulation (MD). Results suggest structural alterations in both mutated forms of TREM2. A large change was noted in the R47H simulation in the complementarity-determining region two (CDR2) binding loop, a proposed binding sites for ligands such as APOE, a smaller change was observed in the R62H model. These differing levels of structural impact could explain the in vitro observed differences in TREM2-ligand binding. Author SummaryA number of mutations have been found in the TREM2 protein in populations of people with Alzheimers and other dementias. Two of these mutations are similar in that the both cause the same coding change in the same domain of the protein. However, they both cause a very different result in terms of risk and in vitro observed changes. Why these two similar mutations are so different is largely unknown. Here we have used a in silico, simulation, approach to understanding the structural changes which occur in both of the mutations. Our results suggest that the mutation which carries a higher risk, but it less commonly observed, has a much larger impact on the protein structure than the mutation which is thought to be less damaging. This structural change is observed at a part of the protein which is thought to code for a binding loop and a change here could have a big impact on the proteins function. Further studies to investigate this binding loop could help not only a better understanding of TREM2s role in the onset of dementia but also possibly provide a target for therapeutics.

systems biology↗

bioRxiv2018

The causal structure of age-dependent limbic decline: fornix white matter glia damage causes hippocampal grey matter damage, not vice versa.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two broad classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative multi-modal MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38 - 71 years). Aging was associated with apparent glia but not axon density damage in the fornix. Mediation analysis unambiguously supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlation between age and hippocampal damage disappears, but not vice versa. Fornix and hippocampal tissue loss were both associated with reductions in episodic memory performance. The implications of these findings for neuroglia and neurodegenerative models of aging and late onset dementia are discussed.

neuroscience↗

bioRxiv2018

Adipokines contribute to central-obesity related reductions in myelin-sensitive MRI indices in the fornix.

Midlife obesity is a risk factor of late onset Alzheimers disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, one possibility is that obesity-related neuroinflammation may contribute to the development of LOAD. Neuroinflammation is closely linked to white matter myelin loss, and this can be measured in vivo with quantitative magnetization transfer (qMT) imaging. Here, we investigated whether differences in obesity measures, i.e., in Waist Hip Ratio (WHR), abdominal visceral and subcutaneous fat volume fractions and Body Mass Index (BMI), were associated with reductions in qMT indices of apparent myelin in temporal white matter pathways involved in LOAD (i.e., the fornix, the parahippocampal cingulum and the uncinate fasciculus compared with whole brain and cortico-spinal white matter) in 166 cognitively healthy individuals (38-71 years of age). Obesity-related effects on myelin-sensitive markers were contrasted with differences in apparent axon density from dual-shell diffusion Neurite Orientation Dispersion and Density Imaging (NODDI). Differences in WHR and in visceral fat volume fractions were negatively correlated with differences in qMT estimates of apparent myelin and tissue metabolism in the fornix but not with any other microstructural components. These correlations were not explained by demographic (age, sex, education), health (hypertension, alcohol consumption, sedentary lifestyle) or genetic (APOE genotype, family history of dementia) risk factors of LOAD. Furthermore, differences in the ratio of plasma concentrations of leptin and adiponectin were also positively correlated with differences in C-Reactive Protein concentrations, and contributed significantly to the correlations between central obesity and myelin-sensitive metrics in the fornix. These results are consistent with the view that visceral fat-related chronic inflammation may damage white matter myelin in limbic regions, known to be vulnerable to LOAD pathology.

neuroscience↗

bioRxiv2018

Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimers Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates.\n\nThree novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423. The ZNF423 gene resides in an Alzheimers disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

genetics↗

bioRxiv2018

Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Late-onset Alzheimers disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3-8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and A{beta} processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7) indicating that additional rare variants remain to be identified.

genetics↗

bioRxiv2018

Increased posterior default mode network activity and structural connectivity in young adult APOE-ε4 carriers: a multi-modal imaging investigation

Young adult APOE-{varepsilon}4 carriers show increased activity in posterior regions of the default mode network (pDMN), but how this is related to structural connectivity is unknown. Thirty young adults (half APOE-{varepsilon}4 carriers, the other half APOE-{varepsilon}3{varepsilon}3/{varepsilon}2{varepsilon}3; mean age 20 years) were scanned using both diffusion and functional magnetic resonance imaging. Diffusion tractography was used to quantify the microstructure (mean diffusivity, MD; fractional anisotropy, FA) of the parahippocampal cingulum bundle (PHCB), which links pDMN and the medial temporal lobe. APOE-{varepsilon}4 carriers had lower MD and higher FA relative to non-carriers in PHCB. Further, PHCB microstructure was selectively associated with pDMN activity during a scene discrimination task known to be sensitive to Alzheimers disease (AD). These findings are consistent with a lifespan view of AD risk, where early-life structural and functional brain changes in specific, vulnerable networks leads to increased neural activity that may ultimately trigger amyloid-{beta} deposition.

neuroscience↗

bioRxiv2017

A common haplotype lowers SPI1 (PU.1) expression in myeloid cells and delays age at onset for Alzheimer’s disease

In this study we used age at onset of Alzheimers disease (AD), cerebrospinal fluid (CSF) biomarkers, and cis-expression quantitative trait loci (cis-eQTL) datasets to identify candidate causal genes and mechanisms underlying AD GWAS loci. In a genome-wide survival analysis of 40,255 samples, eight of the previously reported AD risk loci are significantly (P < 5x10-8) or suggestively (P < 1x10-5) associated with age at onset-defined survival (AAOS) and a further fourteen novel loci reached suggestive significance. Using stratified LD score regression we demonstrated a significant enrichment of AD heritability in hematopoietic cells of the myeloid and B-lymphoid lineage. We then investigated the impact of these 22 AAOS-associated variants on CSF biomarkers and gene expression in cells of the myeloid lineage. In particular, the minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, shows association with higher age at onset of AD (P=8.40x10-6), higher CSF levels of A{beta}42 (P=1.2x10-4), and lower expression of SPI1 in monocytes (P=1.50x10-105) and macrophages (P=6.41x10-87). SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability is enriched within the SPI1 cistromes of monocytes and macrophages, implicating a myeloid PU.1 target gene network in the etiology of AD. Finally, experimentally altered PU.1 levels are correlated with phagocytic activity of BV2 mouse microglial cells and specific changes in the expression of multiple myeloid-expressed genes, including the mouse orthologs of AD-associated genes, APOE, CLU/APOJ, CD33, MS4A4A/MS4A6A, and TYROBP. Our results collectively suggest that lower SPI1 expression reduces AD risk by modulating myeloid cell gene expression and function.

neuroscience↗