Biology subjects

Zetterberg, H.

Publications and source records attributed to Zetterberg, H..

At least 73 records · Page 4Linked to original sources

bioRxiv2020

Mutations in the juxtamembrane segment of the cholesterol-binding site of APP alter its processing and promotes production of shorter, less toxic Aβ peptides.

BackgroundThe brains of patients with Alzheimers disease (AD) reveal increased cellular membrane levels of cholesterol. Correspondingly, we previously showed that elevating levels of membrane cholesterol in neuronal cultures recapitulates early AD phenotypes including excessive cleavage of amyloid {beta} (A{beta}) peptides from the amyloid precursor protein (APP). Here we aimed to evaluate how the presence of a cholesterol-binding site (CBS) in the transmembrane and juxtamembrane regions of APP regulates its processing. MethodsWe generated seven single and two double APP mutants at amino acid positions 22, 26, 28, 29, 33, 39 of the A{beta} sequence changing the charge and/or hydrophobicity of the targeted amino acids. HEK293T cells were transfected with APP constructs and secreted A{beta} peptides were measured using ELISA and mass spectrometry (MS). APP processing in normal and high cholesterol condition, and endocytosis were assessed in stably expressing APPwt and APPK28A HEK293T clones. Finally, we measured the binding of synthetic peptides derived from the A{beta} sequence to cholesterol-rich exosomes purified from control HEK293T cells. ResultsMost mutations triggered a reduction in the production of A{beta}40 and A{beta}42 peptides, whereas only juxtamembrane mutants resulted in the generation of shorter A{beta} peptides. We confirmed by mass spectrometry this specific change in the profile of secreted A{beta} peptides for the most characteristic APPK28A mutant. A transient increase of plasma membrane cholesterol enhanced the production of A{beta}40 by APPWT, an effect absent with APPK28A. The enzymatic activity of -, {beta}- and {gamma}-secretases remained unchanged in cells expressing APPK28A. Similarly, APPK28A subcellular localization in early endosomes did not differ to APPWT. Finally, WT but not CBS mutant A{beta} derived peptides bound to cholesterol-rich exosomes. ConclusionsTaken together, these data reveal a major role of the juxtamembrane region of APP in binding to cholesterol and accordingly in the regulation of APP processing. Binding of cholesterol to K28 could staple APP to the juxtamembrane region thereby permitting access to {gamma}-secretase cleavage at positions 40-42. The APPK28 mutant would lie deeper in the membrane, facilitating the production of shorter A{beta} peptides and unveiling this specific region as a novel target for reducing the production of toxic A{beta} species.

neuroscience↗

bioRxiv2020

Imaging stable isotope labelling kinetics (iSILK) for following spatial Aβ plaque aggregation dynamics in evolving Alzheimers disease pathology

For our understanding of Alzheimers disease (AD) pathophysiology, it is of critical importance to determine how key pathological factors, specifically amyloid {beta} (A{beta}) plaque formation, are interconnected and implicated in neurodegeneration, disease progression and the development of clinical symptoms. Exactly how A{beta} plaque formation is initiated and how the ongoing plaque deposition proceeds is not well understood. This is partly because we can only examine details of the molecular pathology after death in humans, and in mice, we can only examine a particular point in time without any longitudinal information on the fate of individually formed deposits. Herein, we used metabolic labelling of proteins with stable isotopes, together with multimodal imaging mass spectrometry (IMS) for imaging stable isotope labelling kinetics (iSILK) in the APPNL-G-F knock-in mouse model of AD. The aim was to monitor the earliest seeds of A{beta} deposition through ongoing plaque development and track the deposition of A{beta} that is produced later in relation to already deposited plaques. This allowed us to visualize A{beta} peptide aggregation dynamics within individual deposits across different brain regions. We identified the cortex as a primary site of deposition in precipitating plaque pathology. Further, our data show that structural plaque heterogeneity is associated with differential peptide deposition. Specifically, A{beta}1-42 is forming an initial core seed followed by radial outgrowth and late secretion and deposition of A{beta}1-38. Together these data prove the potential of iSILK for probing amyloid protein secretion, processing and aggregation dynamics in AD pathology.

neuroscience↗

bioRxiv2020

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels

BackgroundNeurofilament light (NF-L), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are utilized as biomarkers for Alzheimers disease (AD), to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Here we performed genome-wide association study (GWAS) analyses using all three biomarkers as outcome. MethodsDNA and cerebrospinal fluid (CSF) samples originated from the European Medical Information Framework AD Multimodal Biomarker Discovery (EMIF-AD MBD) study. Overlapping genotype/phenotype data were available for n=671 (NF-L), 677 (YKL-40), and 672 (Ng) individuals. GWAS analyses applied linear regression models adjusting for relevant covariates. FindingsWe identify novel genome-wide significant associations with markers in TMEM106B and CSF levels of NF-L. Additional novel signals were observed with DNA variants in CPOX and CSF levels of YKL-40. Lastly, we confirmed previous work suggesting that YKL-40 levels are regulated by cis protein quantitative trait loci (pQTL) in CHI3L1. InterpretationOur study provides important new insights into the genetic architecture underlying inter-individual variation in all three tested AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

genomics↗

bioRxiv2020

Plasma metabolomics of presymptomatic PSEN1-H163Y mutation carriers: A pilot study

Background and ObjectivePSEN1-H163Y carriers, at the presymptomatic stage, have reduced 18FDG-PET binding in the cerebrum of the brain [1]. This could imply dysfunctional energy metabolism in the brain. In this study, plasma of presymptomatic PSEN1 mutation carriers was analyzed to understand associated metabolic changes. MethodsWe analyzed plasma from non-carriers (NC, n=8) and presymptomatic PSEN1-H163Y mutation carriers (MC, n=6) via untargeted metabolomics using gas and liquid chromatography coupled with mass spectrometry, which identified 1199 metabolites. All the metabolites were compared between MC and NC using univariate analysis, as well as correlated with the ratio of A{beta}1-42/A{beta}1-40, using Spearmans correlation. Altered metabolites were subjected to Ingenuity Pathways Analysis (IPA). ResultsWhen comparing between presymptomatic MC and NC, the levels of 116 different metabolites were altered. Out of 116, only 23 were annotated metabolites, which include amino acids, fatty acyls, bile acids, hexoses, purine nucleosides, carboxylic acids, and glycerophosphatidylcholine species. 1-docosapentaenoyl-GPC, glucose and uric acid were correlated with the ratio of plasma A{beta}1-42/A{beta}1-40 (p < 0.05). ConclusionThis study finds dysregulated metabolite classes, which are changed before the disease onset. Also, it provides an opportunity to compare with sporadic Alzheimers Disease. Observed findings in this study need to be validated in a larger and independent Familial Alzheimers Disease (FAD) cohort. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=31 SRC="FIGDIR/small/093559v1_ufig1.gif" ALT="Figure 1"> View larger version (9K): org.highwire.dtl.DTLVardef@1f5adccorg.highwire.dtl.DTLVardef@653757org.highwire.dtl.DTLVardef@1144ba0org.highwire.dtl.DTLVardef@171272a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Cerebrospinal fluid endo-lysosomal proteins as potential biomarkers for Huntingtons disease.

Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntingtons disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntingtons Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntingtons disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.

neuroscience↗

bioRxiv2020

Impaired adult hippocampal neurogenesis in Alzheimer's disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

SummaryAdult hippocampal neurogenesis (AHN) plays a crucial role in memory processes and is impeded in the brains of Alzheimers disease (AD) patients. However, the molecular mechanisms impacting AHN in AD brain are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a novel mediator of the AHN deficits in AD. The effects of miR-132 are cell-autonomous and its overexpression is proneurogenic in the adult neurogenic niche in vivo and in human neural stem cells in vitro. miR-132 knockdown in wild-type mice mimics neurogenic deficits in AD mouse brain. Restoring miR-132 levels in mouse models of AD significantly restores AHN and relevant memory deficits. Our findings provide mechanistic insight into the hitherto elusive functional significance of AHN in AD and designate miR-132 replacement as a novel therapeutic strategy to rejuvenate the AD brain and thereby alleviate aspects of memory decline.

neuroscience↗

bioRxiv2020

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain

A population of >6 million people worldwide at high risk of Alzheimers disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of {beta}-amyloid-(A{beta})-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A{beta} deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical {beta} and {gamma}-secretase inhibition. We found that T21-organoids secrete increased proportions of A{beta}-preventing (A{beta}1-19) and A{beta}-degradation products (A{beta}1-20 and A{beta}1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in [~]30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

neuroscience↗

bioRxiv2020

Herpes zoster in HIV-1 infection: the role of CSF pleocytosis in secondary CSF escape and discordance

HIV cerebrospinal fluid (CSF) escape is defined by a concentration of HIV-1 RNA in CSF above the lower limit of quantification of the employed assay and equal to or greater than the plasma HIV-1 RNA level in the presence of treatment-related plasma viral suppression, while CSF discordance is similarly defined by equal or higher CSF than plasma HIV-1 RNA in untreated individuals. During secondary CSF escape or discordance disproportionate CSF HIV-1 RNA develops in relation to another infection in addition to HIV-1. We performed a retrospective review of people living with HIV receiving clinical care at Sahlgrenska Infectious Diseases Clinic in Gothenburg, Sweden who developed uncomplicated herpes zoster (HZ) and underwent a research lumbar puncture (LP) within the ensuing 150 days. Based on treatment status and the relationship between CSF and plasma HIV-1 RNA concentrations, they were divided into 4 groups: i) antiretroviral treated with CSF escape (N=4), ii) treated without CSF escape (N=5), iii) untreated with CSF discordance (N=8), and iv) untreated without CSF discordance (N=8). We augmented these with two additional cases of secondary CSF escape related to neuroborreliosis and HSV-2 encephalitis and analyzed these two non-HZ cases for factors contributing to CSF HIV-1 RNA concentrations. HIV-1 CSF escape and discordance were associated with higher CSF white blood cell (WBC) counts than their non-escape (P=0.0087) and non-discordant (P=0.0017) counterparts, and the CSF WBC counts correlated with the CSF HIV-1 RNA levels in both the treated (P=0.0047) and untreated (P=0.002) group pairs. Moreover, the CSF WBC counts correlated with the CSF:plasma HIV-1 RNA ratios of the entire group of 27 subjects (P=<0.0001) indicating a strong effect of the CSF WBC count on the relation of the CSF to plasma HIV-1 RNA concentrations across the entire sample set. The inflammatory response to HZ and its augmenting effect on CSF HIV-1 RNA was found up to 5 months after the HZ outbreak in the cross-sectional sample and, was present for one year after HZ in one individual followed longitudinally. We find that HZ provides a model of secondary CSF escape and discordance. Likely, the inflammatory response to HZ pathology within the CNS provoked local HIV-1 production by enhanced trafficking or activation of HIV-1-infected CD4+ T lymphocytes. Whereas treatment and other systemic factors determined the plasma HIV-1 RNA concentrations, in this setting the CSF WBC counts established the relation of the CSF HIV-1 RNA levels to this plasma set-point. Author summaryHerpes zoster is a neurotropic infection common in people living with HIV. We studied if herpes zoster caused alterations in the cerebrospinal fluid viral (CSF) load when compared with blood levels in patients with and without antiretroviral treatment by studies of the cerebrospinal fluid. HIV-1 CSF escape and discordance were associated with higher CSF white blood cell counts than their non-escape (P=0.0087) and non-discordant (P=0.0017) counterparts, and the CSF white blood cell counts correlated with the CSF HIV-1 RNA levels in both the treated (P=0.0047) and untreated (P=0.002) group pairs. We found that the inflammatory response to herpes zoster pathology within the CSF provoked local HIV-1 production by enhanced trafficking or activation of HIV-1-infected CD4+ T lymphocytes. We suggest that herpes zoster provides a model of secondary HIV CSF escape and HIV CSF/blood discordance, which increase the understanding of HIV central nervous system infection and might be of importance for eradication trials in sanctuary sites such as the central nervous system.

neuroscience↗

bioRxiv2019

Amyloid precursor protein-b facilitates cell adhesion during early development in zebrafish

Understanding the biological function of amyloid beta (A{beta}) precursor protein (APP) beyond its role in Alzheimers disease is emerging. Yet, its function during embryonic development is poorly understood. The zebrafish APP homologue, Appb, is strongly expressed during early development but thus far has only been studied via morpholino-mediated knockdown. Zebrafish enables analysis of cellular processes in an ontogenic context, which is limited in many other vertebrates. We characterized zebrafish carrying a homozygous mutation that introduces a premature stop in exon 2 of the appb gene. We report that appb mutants are significantly smaller until 2dpf and display perturbed enveloping layer (EVL) integrity and cell protrusions at the blastula stage.\n\nMoreover, appb mutants surviving beyond 48 hpf exhibited no behavioral defects at 6 dpf and developed into healthy and fertile adults. The expression of the app-family members, appa and aplp2, was found to be altered in appb mutants. Taken together, we show that appb orchestrates the initial development by supporting the integrity of the EVL, likely by mediating cell adhesion properties. The loss of Appb might be compensated for by other app family members to be able to implement continued normal development.

developmental biology↗

bioRxiv2019

Cross-Sectional and Longitudinal Validation of Serum Neurofilament Light Chain (NfL) as a Biomarker of Parkinson’s Disease Progression

ObjectiveTo assess neurofilament light chain (NfL), as a biomarker for Parkinsons disease (PD). MethodsWe quantified NfL in (1) longitudinal CSF samples from PD, other cognate/neurodegenerative disorders (OND), and healthy controls (HC); (2) a cross-sectional cohort with paired CSF and serum samples from participants with PD, OND, and HC, and (3) a large longitudinal validation cohort with serum samples from PD, OND, HC, prodromal conditions, and mutation carriers. ResultsIn the longitudinal discovery cohort (1) NfL in CSF was highest in OND and higher in PD vs. HC across all visits (p<0.05) but did not change longitudinally. In the cross-sectional cohort (2) paired CSF and serum NfL samples were highly correlated (Spearmans rank [Formula]; p<10^-6). In the large validation cohort (3) mean baseline serum NfL was higher in PD (13{+/-}7.2pg/ml) vs. HC (12{+/-}6.7pg/ml; p=0.0336) and was highest in OND (18{+/-}7pg/ml; p=0.0351). Serum NfL increased longitudinally in PD vs. HC (p<0.01). Longitudinal motor scores were positively longitudinally associated with NfL, whereas some cognitive scores showed a negative longitudinal association with NfL. ConclusionsNfL levels in serum samples are increased in PD vs. HC, increase significantly over time, and correlate with clinical measures of PD severity. Although the specificity of NfL in PD is low and more specific biomarkers are needed, serum NfL is the first blood-based biomarker candidate that could support disease stratification (PD vs. OND), track clinical progression, and possibly assess responsiveness to neuroprotective treatments. NfL as a biomarker of response to neuroprotective interventions remains to be determined. Funding sources for studyPPMI is sponsored by the Michael J. Fox Foundation for Parkinsons Research (MJFF) and is co-funded by MJFF, Abbvie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer and UCB. The funders had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript or in the decision to submit the manuscript for publication. Financial Disclosure/Conflict of Interest concerning the research related to the manuscriptBrit Mollenhauer, Douglas Galasko, Tatiana Foroud, Lana M. Chahine, Christopher S. Coffey, Andrew B. Singleton, Tanya Simuni, Daniel Weintraub, John Seibyl, Arthur W. Toga, and Caroline M. Tanner received funding from The Michael J. Fox Foundation for Parkinsons Research. Mohammed Dakna, Tzu-Ying Liu, Henrik Zetterberg, Sebastian Schade, Roland G. Gera, Wenting Wang, Feng Gao, Niels Kruse, Mark Frasier, Jesse M. Cedarbaum, Samantha J. Hutten, Claudia Trenkwalder, and Danielle Graham report no disclosures.

neuroscience↗

bioRxiv2019

Distinct effects of amyloid and tau deposition on eigenvector centrality during hippocampal down-regulation: a real-time fMRI virtual reality closed-loop neurofeedback study with CSF biomarkers

Hippocampal down-regulation is associated with genetic predisposition to Alzheimers disease (AD), neurodevelopmental processes and disease symptoms. Resting state eigenvector centrality (EC) patterns resemble those of FDG-PET in AD, they can predict self-regulation performance and they are related to functional compensation across the pathophysiological continuum of AD. We acquired cerebrospinal fluid (CSF) biomarkers from a cognitively unimpaired sample at risk for AD (N=48), to investigate the effect of {beta}- amyloid peptide 42 (A{beta}42) and phosphorylated tau (p-Tau) levels on EC during the down-regulation of hippocampal subfield cornu ammonis 1, with real-time fMRI closed-loop neurofeedback. Controlling the effects of confounding variables (age, sex, number of APOE {varepsilon}4 alleles, cognitive reserve, brain reserve and hippocampal down-regulation performance), CSF A{beta}42 levels correlated positively with EC in the anterior cingulate cortex (BA24, BA32) and primary motor cortex (BA4). CSF p-Tau levels correlated with EC positively in the ACC (BA32, BA10) ventral striatum (caudate, nucleus accumbens, putamen) and left primary somatosensory cortex (BA2), as well as negatively in the posterior cingulate cortex, precuneus, cuneus and left frontal pole (BA9). Controlling for CSF biomarkers and other prognosis variables, age correlated negatively with EC in the midcingulate cortex, insula, primary somatosensory cortex (BA2) and inferior parietal lobule (BA40), as well as positively with EC in the inferior temporal gyri. Taken together, we identified patterns of functional connectomics in individuals at risk of AD during hippocampal down-regulation, which resemble those found during resting state at advanced AD stages. Moreover, we provide a standard paradigm to replicate and extend this work on a global level. This opens new avenues for further research applications, which quantify and monitor disease progression, by identifying early alterations in the self-regulation of brain function, with potential for non-invasive prognostic screening.\n\nHighlightsO_LIACC centrality decreases with early A{beta}42\nC_LIO_LIACC centrality increases with p-Tau\nC_LIO_LIPCC centrality decreases with p-Tau\nC_LIO_LIMCC centrality decreases in healthy aging\nC_LI

neuroscience↗

bioRxiv2019

ADSoluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression

Soluble aggregates of amyloid-{beta} (A{beta}) have been associated with neuronal and synaptic loss in Alzheimers disease (AD). However, despite significant recent progress, the mechanisms by which these aggregated species contribute to disease progression are not fully determined. As the analysis of human cerebrospinal fluid (CSF) provides an accessible window into the molecular changes associated with the disease progression, we studied the soluble A{beta} aggregates present in CSF samples from individuals with AD, mild cognitive impairment (MCI) and healthy controls. We found that these aggregates vary structurally and in their mechanisms of toxicity. More small aggregates of A{beta} that can cause membrane permeabilization already found in MCI; in established AD, the aggregates were larger and more prone to elicit a pro-inflammatory response in glial cells. These results suggest that different neurotoxic mechanisms are prevalent at different stages of AD.

neuroscience↗

bioRxiv2019

Plasma pNfH differentiate SBMA from ALS

Background and aimSpinal bulbar muscular atrophy (SBMA) is a progressive adult-onset X-linked neuromuscular disease. Although traditionally considered a motor neuron disorder, recent advances have highlighted a primary myopathic component. We evaluated levels of phosphorylated neurofilament heavy chain (pNfH), a known biomarker for neurodegeneration, in SBMA. Materials and methodsWe collected plasma and serum from 46 SBMA, 50 ALS and 50 healthy control cases, alongside with plasma from a mouse model of SBMA (AR100) and littermate controls. We measured pNfH plasma levels using Single molecule array (Simoa), we assessed functional scales and we gathered demographic data. We analysed data using Mann-Whitney U test, Kruskal-Wallis test and Cox regression analysis. ResultsPlasma pNfH levels were significantly increased in ALS, but, intriguingly, there was no change in SBMA. These results were also confirmed in SBMA mice. The ROC curve highlighted that pNfH levels can effectively distinguish between ALS and SBMA (AUC 0.95). ConclusionsUnexpectedly, levels of pNfH are normal in SBMA, whilst they are increased in ALS, and suggest pNfH could serve as a biomarker to differentiate the two diseases. Further, this finding is in agreement with recent evidence showing that primary muscle damage is a crucial feature in SBMA.

neuroscience↗

bioRxiv2018

Heritability and genetic variance of dementia with Lewy bodies

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinsons disease (PD) or Alzheimers disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

neuroscience↗

bioRxiv2018

The MS4A gene cluster is a key regulator of soluble TREM2 and Alzheimer disease risk

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in the cerebrospinal fluid (CSF) have been associated with Alzheimer disease (AD) status. TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may help reveal biological mechanisms underlying AD and identify novel therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 levels. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with higher CSF sTREM2 levels (rs1582763; P = 1.15x10-15) and replicated in independent datasets. The variants associated with increased levels of sTREM2 are also associated with reduced AD risk and delayed age-at-onset. Rs1582763 influences expression of MS4A4A and MS4A6A in multiple tissues, suggesting that one or both of these genes are important for regulating sTREM2. MS4A genes encode transmembrane proteins that may play a role in intracellular protein trafficking in microglia. We used human macrophages to begin to test the relationship between MS4A4A and TREM2 and found that they co-localize intracellularly and that antibody-mediated targeting of MS4A4A reduces sTREM2. Thus, genetic, molecular, and cellular findings suggest that MS4A4A regulates sTREM2. These findings also provide a mechanistic explanation of the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 is involved in sporadic AD risk in general, not only in TREM2 risk-variant carriers.

genomics↗

bioRxiv2018

Prion protein quantification in cerebrospinal fluid as a tool for prion disease drug development

Reduction of native prion protein (PrP) levels in the brain is an attractive and genetically validated strategy for the treatment or prevention of human prion diseases. However, clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction, in the central nervous system (CNS) of a living patient. Here we evaluate the potential of enzyme-linked immunosorbent assay (ELISA)-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS-derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test-retest reliability (mean coefficient of variation 13% in samples collected 8-11 weeks apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, enabling the development of prion disease therapeutics with this mechanism of action.

molecular biology↗

bioRxiv2018

Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome

INTRODUCTIONDown syndrome (DS) may be considered a genetic form of Alzheimers disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions.\n\nMETHODSWe measured blood NF-L concentration in 100 adults with DS using Simoa NF-light(R) assays, and examined relationships with age, and cross-sectional and longitudinal dementia diagnosis.\n\nRESULTSNF-L levels increased with age (Spearmans rho = 0.789, p<0.001), with a steep increase after age 40, and were predictive of dementia status (p=0.022 adjusting for age, sex, and APOE4) but showed no relationship with longstanding epilepsy or premorbid ability. Baseline NF-L levels were associated with longitudinal dementia status.\n\nDISCUSSIONNF-L is a biomarker for neurodegeneration in DS, with potential for use in future clinical trials to prevent or delay dementia.\n\nResearch in contextO_ST_ABSSystematic reviewC_ST_ABSThe authors reviewed the literature using PubMed searches supplemented with our knowledge of pending papers in this research area. While blood NF-L has been associated with clinical features of progression in a number of neurodegenerative conditions, we have not identified any reports of NF-L associated with cognitive decline in DS, a genetic form of AD.\n\nInterpretationOur findings demonstrate the potential utility of NF-L as a blood biomarker of neurodegeneration in DS, a population that may not be able to tolerate more invasive procedures such as neuroimaging and lumbar punctures to track progression.\n\nFuture directionsThe association between NF-L and other markers of longitudinal AD progression should be explored further in future work.

molecular biology↗

bioRxiv2018

CSF biomarkers are differentially related to structural and functional changes in dementia of the Alzheimer’s type

The two cardinal pathologies of Alzheimers disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimers type. Interrelationships were analysed between cerebrospinal fluid (CSF) biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks.

neuroscience↗