Biology subjects

Blennow, K.

Publications and source records attributed to Blennow, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Neurostructural and molecular evidence of advanced brain aging in rheumatoid arthritis

Chronic systemic inflammation has been implicated in age-related neurodegeneration, but whether rheumatoid arthritis (RA) is associated with accelerated brain aging remains unclear. We combined structural magnetic resonance imaging (MRI), circulating neurodegeneration biomarkers, and peripheral monocyte transcriptomics to investigate brain aging in RA across two independent cohorts. A brain-age prediction model trained in healthy controls from the IXI imaging dataset was applied to RA patient cohorts from Gothenburg (n = 71) and Glasgow (n = 50). RA was associated with significantly elevated corrected brain-age gap relative to healthy controls (+6.5 years, 95% CI 4.2-8.8 years, p = 1.2 x 10-7), with substantially stronger effects in patients [≥]60 years. Older RA patients demonstrated a significant ventricular enlargement together with reduced frontal and parietal lobe volumes. Serum brain-derived tau and glial fibrillary acidic protein levels were elevated in RA. The increased brain-age gap was associated with altered myeloid transcriptional signatures. These findings demonstrate that RA is associated with age-related neurostructural alterations consistent with accelerated brain aging.

neuroscience↗

bioRxiv2025

Beyond adoption rates: Farmer motivations and communication needs in straw management decision-making

Sustainable bioenergy is central to climate change mitigation, yet biomass supply depends not only on biophysical and economic assessments but also on farmers decision-making. Straw from cereal and oilseed crops can support renewable energy, but its availability is constrained by on-farm uses, management practices, and farmers access to knowledge of sustainable soil management. Because straw removal affects soil organic carbon (SOC) stocks, which underpins soil fertility, nutrient cycling, and carbon sequestration, understanding farmers motivations and informational needs is critical to support sustainable straw management. We examined the determinants of straw management among farmers in Scania County, southern Sweden, testing three hypotheses: that manure application increases the likelihood of straw removal, that a higher proportion of leased land promotes straw removal, and that humus-rich soils are associated with a higher probability of straw removal. Survey data from 2021 were analysed using Bayesian Additive Regression Trees (BART) and permutation tests, incorporating farmers expected utility. Results show that manure application increases removal probability, whereas a higher share of leased land reduces it. Removal was most frequent on soils with intermediate humus content. Cluster analysis identified three farmer profiles, revealing heterogeneous motivations and knowledge gaps, particularly regarding soil humus content, and underscoring the need for context-specific communication strategies. These findings demonstrate that similar straw management behaviours can arise from diverse motivations and local conditions. Linking expectations, soil properties, and practices provides actionable insights for targeted advisory and policy measures that balance agronomic and economic outcomes with long-term SOC-mediated fertility, carbon sequestration, and ecosystem services.

scientific communication and education↗

bioRxiv2025

A methodological approach to developing evidence-based communication guidelines for Populus spp. cultivation on agricultural land

This study developed and applied a methodology and framework to analyse decision-making and identify communication needs related to Populus spp. cultivation on agricultural land in southern Sweden, where adoption remains limited despite significant biomass potential. By comparing farmers willingness and actual cultivation decisions, and linking these to expectations on economic, agronomic, and environmental outcomes, we moved beyond attitudes to analyse choices. We used Bayesian Additive Regression Trees (BART) to predict cultivation decisions and willingness to cultivate using Net Value of Expected Impact (NVEI) as a predictor. Integrating decision-making with willingness revealed drivers of adoption and barriers persisting despite positive attitudes. NVEI scores strongly predicted both willingness and cultivation decisions, with regional contrasts evident. In the Forested region, farmers anticipated greater economic and agronomic benefits but had lower expectations for biodiversity, suggesting a knowledge gap and a need for communication providing comparative evidence on biodiversity benefits. In the Lowland region, higher expectations for environmental benefits highlight the need for tailored information on biodiversity, landscape value, and ecological connectivity. Low scores for workload and management ease across all groups indicate uncertainty about practical aspects, supporting the need for targeted communication. Overall, regionally tailored, evidence-based guidelines can support informed decision-making.

scientific communication and education↗

bioRxiv2025

Identifying gaps between scientific and local knowledge in climate change adaptation for northern European agriculture

Climate change impacts agriculture in complex and regionally specific ways. In temperate regions such as southern Sweden, it presents both opportunities, such as longer growing seasons, and challenges, including increased drought and heat stress. This study examined how Swedish agriculture is adapting to climate change, using the extreme 2018 drought and heatwave as a critical case to explore both immediate responses and longer-term preparedness in crop production systems. We compared scientific and local knowledge through a systematic scoping review of peer-reviewed literature from northern Europe, a workshop with project scientists, and a participatory workshop with farmers. The study aimed to identify gaps between scientific and local understandings of climate change adaptation, particularly in how extreme events influence decision-making and preparedness. Using a transdisciplinary, problem-feeding approach, we compared how farmers and scientists conceptualise crisis response and long-term adaptation, employing influence diagrams to visualise their understandings. Our review found that much scientific work focuses on short-term coping strategies, such as feed substitution or altered irrigation, while longer-term adaptation remains underexplored. In contrast, farmers emphasized context specific actions grounded in their farm operations, highlighting socio-economic and administrative constraints, whereas scientists tended to propose generalisable technology-oriented strategies. These differences underscore the importance of integrating both experiential and scientific knowledge to co-develop more effective adaptation responses. The study lays the foundation for a targeted, large-scale survey to explore farmer motivations, perceptions of risk and opportunity, and adaptive capacities across diverse contexts. Our findings highlight the need to move beyond reactive measures and investigate anticipatory strategies that foster and enable adaptive capacity. Here we demonstrate that supporting long-term adaptation in agriculture will require inclusive, evidence-based approaches that incorporate perspectives from farmers, advisors, scientists, and public authorities alike.

scientific communication and education↗

bioRxiv2025

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimers disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. Mechanistically, ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3{beta} inhibition. Together, our study links ImP to hallmarks of neurodegeneration and suggest that targeting ImP may represent a potential strategy to modify ADRD risk.

pathology↗

bioRxiv2025

Associations between fluid biomarkers and PET imaging (UCB-J) of synaptic pathology in Alzheimer's disease

INTRODUCTIONPositron Emission Tomography (PET) imaging with ligands for synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising methodology for measuring synaptic density in Alzheimers disease (AD). We investigate the relationship between SV2A PET and CSF synaptic protein changes of AD patients. METHODTwenty-one participants with early AD and 7 cognitively normal (CN) individuals underwent [11C]UCB-J PET. We used mass spectrometry to measure a panel of synaptic proteins in CSF. RESULTSIn the AD group, higher levels of syntaxin-7 and PEBP-1 were associated with lower global synaptic density. In the total sample, lower global synaptic density was associated with higher levels of AP2B1, neurogranin, {gamma}-synuclein, GDI-1, PEBP-1, syntaxin-1B, and syntaxin-7 but not with the levels of the neuronal pentraxins or 14-3-3 zeta/delta. CONCLUSIONReductions of synaptic density found in AD compared to CN participants using [11C]UCB-J PET were observed to be associated with CSF biomarker levels of synaptic proteins.

neuroscience↗

bioRxiv2024

Data-driven evaluation of suitable immunogens for improved antibody selection

Antibodies are indispensable in laboratory and clinical applications due to their high specificity and affinity for protein antigens. However, selecting the right protein fragments as immunogens for antibody production remains challenging. Leveraging the Human Protein Atlas, this study systematically evaluates immunogen properties aiming to identify key factors that influence their suitability. Antibodies were classified as successful or unsuccessful based on standardized validation experiments, and the structural and functional properties of their immunogens were analyzed. Results indicated that longer immunogens often resulted in more successful but less specific antibodies. Shorter immunogens (50 residues or fewer) with disordered or unfolded regions at the N- or C-terminus and long coil stretches, were more likely to generate successful antibodies. Conversely, immunogens with high beta sheet content, multiple secondary structure elements, transmembrane regions, or disulfide bridges were associated with poorer antibody performance. Post-translational modification sites within immunogens appeared to mark beneficial regions for antibody generation. To support antibody selection, a novel R package, immunogenViewer, was developed, enabling researchers to easily apply these insights when immunogen sequences are disclosed. By providing a deeper understanding of immunogen suitability, this study promotes the development of more effective antibodies, ultimately addressing issues of reproducibility and reliability in antibody-based research. The findings are highly relevant to the research community, as end-users often lack control over the immunogen selection process in antibody production.

bioinformatics↗

bioRxiv2024

Isotope Encoded Chemical Imaging Identifies Amyloid Plaque Age Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity

It is of critical importance to our understanding of Alzheimers disease (AD) pathology to determine how key pathological factors are interconnected and implicated in nerve cell death, clinical symptoms, and disease progression. The formation of extracellular beta-amyloid (A{beta}) plaques is the major pathological hallmark of AD and A{beta} has been suggested to be a critical inducer of AD, driving disease pathogenesis. Exactly how A{beta} plaque formation begins and how ongoing plaque deposition proceeds and initiates subsequent neurotoxic mechanisms is not well understood. The primary aim of our research is to elucidate the biochemical processes underlying early A{beta} plaque formation in brain tissue. We recently introduced a chemical imaging paradigm based on mass spectrometry imaging (MSI) and metabolic isotope labelling to follow stable isotope labelling kinetics (iSILK) in vivo to track the in vivo build-up and deposition of A{beta}. Herein, knock-in A{beta} mouse models (AppNL-F) that develop A{beta} pathology gradually are metabolically labeled with stable isotopes. This chemical imaging approach timestamps amyloid plaques during the period of initial deposition allowing the fate of aggregating A{beta} species from before and during the earliest events of plaque pathology through plaque maturation to be tracked. To identify the molecular and cellular response to plaque maturation, we integrated iSILK with single plaque transcriptomics performed on adjacent tissue sections. This enabled changes in gene expression to be tracked as a function of plaque age (as encoded in the A{beta} peptide isotopologue pattern) distinct from changes due to the chronological age or pathological severity. This approach identified that plaque age correlates negatively with gene expression patterns associated with synaptic function as early as in 10-month-old animals but persists into 18 months. Finally, we integrated hyperspectral confocal microscopy into our multiomic approach to image amyloid structural isomers, revealing a positive correlation between plaque age and amyloid structural maturity. This analysis identified three categories of plaques, each with a distinct impact on the surrounding microenvironment. Here, we identified that older, more compact plaques were associated with the most significant synapse loss and toxicity. These data show how isotope-encoded MS imaging can be used to delineate A{beta} toxicity dynamics in vivo. Moreover, we show for the first time a functional integration of dynamic MSI, structural plaque imaging and whole genome-wide spatial transcriptomics at the single plaque level. This multiomic approach offers an unprecedented combination of temporal and spatial resolution enabling a description of the earliest events of precipitating amyloid pathology and how A{beta} modulates synaptotoxic mechanisms.

neuroscience↗

bioRxiv2024

Altered T cell reactivity to β-amyloid-related antigens in early Alzheimer's disease

There is growing evidence that the adaptive immune system and neurodegenerative Alzheimers disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and cerebrospinal fluid from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing, in vitro T cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+ T helper cell response towards {beta}- amyloid peptide and display an early enrichment of cytotoxic CD8+ effector/TEMRA cells in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T cells. Conversely, in MCI due to AD, we observed increased frequencies of CD8+ effector/TEMRA cells in the periphery, characterized by a pro-inflammatory gene expression profile and an overall decrease in antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial in the preclinical stage to promote specific CD4+ T cell responses, while in MCI it may be important to therapeutically target CD8+ T cell responses if these prove to be harmful.

immunology↗

bioRxiv2024

Chemical imaging signatures delineate heterogeneous amyloid plaque populations across the Alzheimers disease spectrum

Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimers disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic A{beta} plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated A{beta} compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct A{beta} signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of A{beta}x-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more A{beta}x-40 and less A{beta}x-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the A{beta} peptide content in coarse grain plaques resembled that of vascular A{beta} deposits (CAA) though with relatively higher levels of A{beta}1-42 and pyroglutamated A{beta}x-40 and A{beta}x-42 species in coarse grain plaques. This is the first of its kind study on spatial in situ biochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.

neuroscience↗

bioRxiv2024

PTPRS is a novel marker for early tau pathology and synaptic integrity in Alzheimer's disease

We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimers disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimers disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early tau pathology and synaptic degeneration in Alzheimers disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower P-tau181 and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimers disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.

neuroscience↗

bioRxiv2024

Changes in Cerebrospinal Fluid Proteins across the Spectrum of Untreated and Treated Chronic HIV-1 Infection

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers that included uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of the CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes that includes highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of neuroasymptomatic systemic HIV-1 progression, including two common patterns, designated as lymphoid and myeloid patterns, related to the principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, and further the mechanistic understanding of HIV-1-related CNS pathobiology.

microbiology↗

bioRxiv2024

Subtypes of brain change in aging and their associations with cognition and Alzheimer's disease biomarkers

Structural brain changes underly cognitive changes in older age and contribute to inter-individual variability in cognition. Here, we assessed how changes in cortical thickness, surface area, and subcortical volume, are related to cognitive change in cognitively unimpaired older adults using structural magnetic resonance imaging (MRI) data-driven clustering. Specifically, we tested (1) which brain structural changes over time predict cognitive change in older age (2) whether these are associated with core cerebrospinal fluid (CSF) Alzheimers disease (AD) biomarkers phosphorylated tau (p-tau) and amyloid-{beta} (A{beta}42), and (3) the degree of overlap between clusters derived from different structural features. In total 1899 cognitively healthy older adults (50 - 93 years) were followed up to 16 years with neuropsychological and structural MRI assessments, a subsample of which (n = 612) had CSF p-tau and A{beta}42 measurements. We applied Monte-Carlo Reference-based Consensus clustering to identify subgroups of older adults based on structural brain change patterns over time. Four clusters for each brain feature were identified, representing the degree of longitudinal brain decline. Each brain feature provided a unique contribution to brain aging as clusters were largely independent across modalities. Cognitive change and baseline cognition were best predicted by cortical area change, whereas higher levels of p-tau and A{beta}42 were associated with changes in subcortical volume. These results provide insights into the link between changes in brain morphology and cognition, which may translate to a better understanding of different aging trajectories.

neuroscience↗

bioRxiv2024

An interim exploratory biomarker analysis of a Phase 2 clinical trial to assess the impact of CT1812 in Alzheimers disease

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimers disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (A{beta}) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing Phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in patients with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics can detect more than 2,000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812. HIGHLIGHTSO_LIEffects of CT1812 on AD patients were investigated in a randomized Phase 2 clinical trial C_LIO_LIPharmacodynamic biomarkers of CT1812 were identified through unbiased analysis of proteomics quantitation data acquired using TMT Mass Spectrometry (TMT-MS) C_LIO_LICT1812 normalized a set of biomarkers altered in AD C_LIO_LIFindings provide proof of mechanism that CT1812 impacts synapse, inflammation, amyloid-related processes C_LI

neuroscience↗

bioRxiv2023

Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases

Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimers disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related mechanisms which vary between individuals, such as CSF production and clearance rates. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our novel reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.

neuroscience↗

bioRxiv2023

Revealing the combined roles of Abeta and tau in Alzheimer's disease via a pathophysiological activity decoder

Neuronal dysfunction and cognitive deterioration in Alzheimers disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we introduce personalized brain activity models incorporating functional MRI, amyloid-{beta} (A{beta}) and tau-PET from AD-related participants (N=132). Within the model assumptions, electrophysiological activity is mediated by toxic protein deposition. Our integrative subject-specific approach uncovers key patho-mechanistic interactions, including synergistic A{beta} and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP). Furthermore, our results reproduce hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with A{beta}-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions.

neuroscience↗

bioRxiv2023

Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations

Alzheimers disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, including the aggregated forms, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. While in animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, it is unclear whether the tau species present in CSF will modulate neural activity. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input-output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/525362v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@13f564forg.highwire.dtl.DTLVardef@13b75cborg.highwire.dtl.DTLVardef@b27dbaorg.highwire.dtl.DTLVardef@5c68c0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

APOE ε4 gene dose effect on imaging and blood biomarkers of glial reactivity and β-amyloid pathology

Increased reactivity of microglia and astrocytes is known to be present at various stages of the Alzheimers continuum but their relationship with core Alzheimers disease pathology in the preclinical stages is less clear. We investigated glial reactivity and {beta}-amyloid pathology in cognitively unimpaired APOE {varepsilon}4 homozygotes, heterozygotes and non-carriers using 11C-PK11195 PET (targeting 18-kDa translocator protein), 11C-PiB PET (targeting {beta}-amyloid), brain MRI, and a preclinical cognitive composite (APCC). Plasma glial fibrillary acidic protein (GFAP) by and plasma A{beta}1-42/1-40 were measured using single molecule array and immunoprecipitation combined with mass spectrometry, respectively. We observed that (i) 11C-PiB-binding was significantly higher in APOE {varepsilon}4 homozygotes compared with non-carriers in all evaluated regions, (ii) regional 11C-PK11195-binding did not differ between the APOE {varepsilon}4 gene doses or between A{beta}-positive and -negative individuals, and (iii) higher 11C-PK11195-binding and plasma GFAP were associated with lower hippocampal volume, and elevated 11C-PiB-binding and plasma GFAP concentration with lower APCC scores. Increased glial reactivity might emerge in later stages of preclinical Alzheimers disease in parallel with early neurodegenerative changes.

neuroscience↗