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A human tau seeded neuronal cell model recapitulates molecular responses associated with Alzheimer's disease.

ABSTRACT: Cellular models recapitulating features of tauopathies are useful tools to investigate the causes and consequences of tau aggregation and the identification of novel treatments. We seeded rat primary cortical neurons with tau isolated from Alzheimer's disease brains to induce a time-dependent increase in endogenous tau inclusions. Transcriptomics of seeded and control cells identified 1075 differentially expressed genes (including 26 altered at two time points). These were enriched for lipid/steroid metabolism and neuronal/glial cell development genes. 50 genes were correlated with tau inclusion formation at both transcriptomic and proteomic levels, including several microtubule and cytoskeleton-related proteins such as Tubb2a, Tubb4a, Nefl and Snca. Several genes (such as Fyn kinase and PTBP1, a tau exon 10 repressor) interact directly with or regulate tau. We conclude that this neuronal model may be a suitable platform for high-throughput screens for target or hit compound identification and validation.

SUBMITTER: Ficulle E

PROVIDER: S-EPMC8854741 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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A human tau seeded neuronal cell model recapitulates molecular responses associated with Alzheimer's disease.

Ficulle Elena E Kananathan Sarubini S Airey David D Gharbi Severine I SI Humphryes-Kirilov Neil N Scherschel James J Dunbar Charlotte C Eastwood Brian J BJ Laing Emma E Collier David A DA Bose Suchira S

Scientific reports 20220217 1

Cellular models recapitulating features of tauopathies are useful tools to investigate the causes and consequences of tau aggregation and the identification of novel treatments. We seeded rat primary cortical neurons with tau isolated from Alzheimer's disease brains to induce a time-dependent increase in endogenous tau inclusions. Transcriptomics of seeded and control cells identified 1075 differentially expressed genes (including 26 altered at two time points). These were enriched for lipid/ste ...[more]

PMID: 35177665

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Project description:Background: Alzheimer's disease involves widespread and progressive deposition of misfolded protein tau (τ), first appearing in the entorhinal cortex, coagulating in longer polymers and insoluble fibrils. There is mounting evidence for "prion-like" trans-neuronal transmission, whereby misfolded proteins cascade along neuronal pathways, giving rise to networked spread. However, the cause-effect mechanisms by which various oligomeric τ species are produced, aggregate, and disseminate are unknown. The question of how protein aggregation and subsequent spread lead to stereotyped progression in the Alzheimer brain remains unresolved. Materials and Methods: We address these questions by using mathematically precise parsimonious modeling of these pathophysiological processes, extrapolated to the whole brain. We model three key processes: τ monomer production; aggregation into oligomers and then into tangles; and the spatiotemporal progression of misfolded τ as it ramifies into neural circuits via the brain connectome. We model monomer seeding and production at the entorhinal cortex, aggregation using Smoluchowski equations; and networked spread using our prior Network-Diffusion model. Results: This combined aggregation-network-diffusion model exhibits all hallmarks of τ progression seen in human patients. Unlike previous theoretical studies of protein aggregation, we present here an empirical validation on in vivo imaging and fluid τ measurements from large datasets. The model accurately captures not just the spatial distribution of empirical regional τ and atrophy but also patients' cerebrospinal fluid phosphorylated τ profiles as a function of disease progression. Conclusion: This unified quantitative and testable model has the potential to explain observed phenomena and serve as a test-bed for future hypothesis generation and testing in silico. Impact statement The presented aggregation-network-diffusion model exhibits all hallmarks of tau progression in human patients; it accurately captures not just the spatial distribution of empirical regional tau and atrophy but also patients' cerebrospinal fluid phosphorylated tau profiles. Thus, it serves to fill a theoretical gap between microscopic biophysical processes and empirical macroscopic measurements of pathological patterns in Alzheimer's disease. This unified quantitative and testable model has the potential to explain observed phenomena and serve as a test-bed for future hypothesis generation and testing in silico.

Project description:Pathological tau spreads throughout the brain along neuronal connections in Alzheimer's disease (AD), but the mechanisms that underlie this process are poorly understood. Given the high incidence and deleterious consequences of epileptiform activity in AD, we hypothesized neuronal hyperactivity and seizures are key factors in tau spread. To examine these interactions, we created a novel mouse model involving the cross of targeted recombination in active populations (TRAP) mice and the 5 times familial AD (5XFAD; 5X-TRAP) model allowing for the permanent fluorescent labelling of neuronal activity. To establish a causal role of seizures in tau spread, we seeded mice with human AD brain-derived tau lysate and induced seizures with pentylenetetrazol (PTZ) kindling. Comprehensive brain mapping of tau pathology and neuronal activity revealed that basal hyperactivity in 5X-TRAP mice was associated with increased tau spread, which was exacerbated by seizure induction through activated networks and correlated with memory deficits. Computational modeling revealed that anterograde tau spread was elevated in 5X-TRAP mice and that regional neuronal activity was predictive of tau spread to that brain region. On a cellular level, we found that in both saline and PTZ-treated 5X-TRAP mice, hyperactive neurons disproportionately contributed to the spread of tau. Further, we found that Synaptogyrin-3, a synaptic vesicle protein that interacts with tau, was increased following PTZ kindling in 5X-TRAP mice, possibly indicative of a synaptic mechanism underlying seizure-exacerbated tau spread. Importantly, postmortem AD brain tissue from patients with a history of seizures showed increased tau pathology in patterns indicative of increased spread and increased Synaptogyrin-3 levels compared to those without seizures. Overall, our study identifies neuronal hyperactivity and seizures as key factors underlying the pathobiological and cognitive progression of AD. Therapies targeting these factors should be tested clinically to slow tau spread and AD progression.

Project description:Tauopathies are a class of neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, which are associated with the pathological aggregation of tau protein into neurofibrillary tangles (NFT). Studies have characterized tau as a "prion-like" protein given its ability to form distinct, stable amyloid conformations capable of transcellular and multigenerational propagation in clonal fashion. It has been proposed that progression of tauopathy could be due to the prion-like propagation of tau, suggesting the possibility that end-stage pathologies, like NFT formation, may require an instigating event such as tau seeding. To investigate this, we applied a novel human induced pluripotent stem cell (hiPSC) system we have developed to serve as a human neuronal model. We introduced the tau repeat domain (tau-RD) with P301L and V337M (tau-RD-LM) mutations into hiPSC-derived neurons and observed expression of tau-RD at levels similar to total tau in postmortem AD brains. Tau aggregation occurred without the addition of recombinant tau fibrils. The conditioned media from tau-RD cultures contained tau-RD seeds, which were capable of inducing aggregate formation in homotypic mode in non-transduced recipient neuronal cultures. The resultant NFTs were thioflavin-positive, silver stain-positive, and assumed fibrillary appearance on transmission electron microscopy (TEM) with immunogold, which revealed paired helical filament 1 (PHF1)-positive NFTs, representing possible recruitment of endogenous tau in the aggregates. Functionally, expression of tau-RD caused neurotoxicity that manifested as axon retraction, synaptic density reduction, and enlargement of lysosomes. The results of our hiPSC study were reinforced by the observation that Tau-RD-LM is excreted in exosomes, which mediated the transfer of human tau to wild-type mouse neurons in vivo. Our hiPSC human neuronal system provides a model for further studies of tau aggregation and pathology as well as a means to study transcellular propagation and related neurodegenerative mechanisms.

Project description:BackgroundIncreased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer's disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels.MethodsWe performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer's Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study.ResultsWe found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood-brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins.ConclusionsCSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood-brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

Dataset Information

A human tau seeded neuronal cell model recapitulates molecular responses associated with Alzheimer's disease.

Publications

A human tau seeded neuronal cell model recapitulates molecular responses associated with Alzheimer's disease.

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