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Elevated Cerebrospinal Fluid Ubiquitin Carboxyl‐Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers
ObjectiveTo identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.MethodsCross‐sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non‐carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre‐defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age‐matched non‐carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.ResultsUbiquitin carboxyl‐hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age‐matched non‐carriers (log2fold change 0.20, FDR‐adjusted p‐value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl‐hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007).InterpretationElevated cerebrospinal fluid ubiquitin carboxyl‐hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2025;97:449–459
Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease
AbstractThe abnormal assembly of tau protein in neurons is a pathological hallmark of multiple neurodegenerative diseases, including Alzheimer’s disease (AD). Assembled tau associates with extracellular vesicles (EVs) in the central nervous system of individuals with AD, which is linked to its clearance and prion-like propagation. However, the identities of the assembled tau species and EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from individuals with AD. We found tau filaments composed mainly of truncated tau that were enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.
In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds
Abstract Tau pathology is a hallmark of several neurodegenerative diseases, including frontotemporal dementia and Alzheimer’s disease. However, the sequence of events and the form of tau that confers toxicity are still unclear, due in large part to the lack of physiological models of tauopathy initiation and progression in which to test hypotheses. We have developed a series of targeted mice expressing frontotemporal-dementia-causing mutations in the humanized MAPT gene to investigate the earliest stages of tauopathy. MAPT Int10+3G>A and MAPT S305N;Int10+3G>A lines show abundant hyperphosphorylated tau in the hippocampus and entorhinal cortex, but they do not develop seed-competent fibrillar structures. Accumulation of hyperphosphorylated tau was accompanied by neurite degeneration, loss of viable synapses and indicators of behavioral abnormalities. Our results demonstrate that neuronal toxicity can occur in the absence of fibrillar, higher-order structures and that tau hyperphosphorylation is probably involved in the earliest etiological events in tauopathies showing isoform ratio imbalance.
Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease
SUMMARYThe abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer’s disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from AD patients. We found filaments of truncated tau enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.
Differences in neuronal ciliation rate and ciliary content revealed by systematic imaging-based analysis of hiPSC-derived models across protocols.
IntroductionCiliopathies are a group of human Mendelian disorders caused by dysfunction of primary cilia, small quasi-ubiquitous sensory organelles. Patients suffering from ciliopathies often display prominent neurodevelopmental phenotypes, underscoring the importance of primary cilia during development and for function of the central nervous system (CNS). Human tissues, in particular from the CNS, are very hard to obtain for research. Patient derived- or genetically engineered human induced pluripotent stem cells (hiPSCs) are therefore a precious resource for investigating the role of cilia in human neurons.MethodsIn this study we used a variety of 2D and 3D neuronal differentiation protocols in multiple hiPSC lines and systematically analyzed ciliation rates and ciliary length in hiPSCs, neural stem cells (NSCs), immature and different types of mature neurons using immunofluorescence.ResultsWe found that ciliation rate varied substantially between cell lines and differentiation protocols. Moreover, ciliation rate depended on differentiation stage, being maximal in NSCs and decreasing with neuronal maturation. In various types of mature neurons obtained with different protocols, we found ciliation rates to be as low as ∼10%. Neuronal density also played an important role, with higher ciliation in denser cultures. We further investigated the ciliary protein content in these cells at different differentiation stages using commonly used antibodies against ARL13B, INPP5E, AC3 and GPR161. Cilia in hiPSCs, NSCs and neurons were all positive for ARL13B, with a decreasing trend in intensity in more mature neurons. Likewise, INPP5E was present in all cilia analyzed, while AC3 positivity increased as maturation proceeded. Interestingly, we found that while GPR161 signal almost completely disappeared from cilia upon Sonic hedgehog (SHH) stimulation in NSCs and immature neurons, this was not the case in more mature neurons, suggesting a possible developmental time window for cilia-dependent SHH signaling.ConclusionTaken together, our results provide a systematic description of cilia in hiPSC-derived neuronal cells generated with different protocols, underscoring the importance of selecting the optimal model system and controls for investigating primary cilia in hiPSC-derived neuronal cells.
A fluid-walled microfluidic platform for human neuron microcircuits and directed axotomy
In vivo, different neurons make directional connections; however, most in vitro models fail to capture such connectivity. We use microfluidics with fluid walls to study neuronal circuits in vitro in ways that fit into existing bio-medical workflows.
An impedimetric assay of α-synuclein autoantibodies in early stage Parkinson's disease
A careful quantification of autoantibodies raised against the primary protein component of Lewy bodies enables a statistically significant differentiation between early stage Parkinson's patients and controls.