iPSC-Induced Neurons with the V337M MAPT Mutation are Selectively Vulnerable to Caspase-Mediated Cleavage of Tau and Apoptotic Cell Death
Year: 2021
Type: article
Abstract: Background: Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Tau proteolysis by caspases, including caspase-6, represents an understudied PTM that may increase neurotoxicity and tau self-aggregation. Methods: To elucidate the presence and temporal course of caspase activation, tau cleavage, and neuronal death, we generated two novel epitope (neoepitope) monoclonal antibodies (mAbs) against caspase-6 tau proteolytic sites. We evaluated tau cleavage and response to apoptotic stress in cortical neurons derived from induced pluripotent stem cells (iPSCs) with frontotemporal dementia (FTD)-causing V337M MAPT mutation. We tested the neuroprotective effect of caspase inhibitors in the induced neurons. We also demonstrated the presence of the tau neoepitopes in postmortem brains from an individual with FTD (V337M MAPT) and an individual with AD, compared to a healthy control. Results: FTLD V337M MAPT and AD postmortem brains showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau and phosphorylated (p)-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by inhibition of effector caspases. Conclusions: Culturing iPSC-derived neurons for three months exposes age-related tau pathologies, including caspase-mediated cleavage, that are also observed in human postmortem brains with abnormal tau deposition. Neoepitope antibodies to caspase-cleaved tau may serve as biomarkers of tau pathology. Furthermore, caspases could be viable therapeutic targets for tau pathogenesis in FTLD and other tauopathies.
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis, Linking tau proteostasis with neuronal activity in FTD, G1964544685, Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis, Uncovering mechanisms of selective vulnerability by CRISPR-based genetic screens, Caspases and proteasome as determinants of opposite neuronal fate in AD, The role of cell death pathways in mediating neuronal loss during the earliest stages of Alzheimer disease, G692441771, G7282017350, G898313041, G9000101129, Investigating regional and cellular vulnerabilities to tau pathology in young-onset Alzheimer's disease, Frontotemporal Dementia: Genes, Images, and Emotions, Uncovering the Genetic Mechanisms of the Chromosome 17q21.31 Tau Haplotype on Neurodegeneration Risk in FTD and PSP, Neuropathological changes underlying clinical heterogeneity in Alzheimer dise, Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and PSP, New Approaches to Dementia Heterogeneity, Formation and Propagation of Tau Oligomeric Strains in Alzheimer's Disease, New Approaches to Dementia Heterogeneity
OpenAlex ID: W4400842794