Caspase-6-cleaved tau is relevant in Alzheimer's disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications
| Autor: | Panos Theofilas, Antonia M. H. Piergies, Ian Oh, Yoo Bin Lee, Song Hua Li, Felipe L. Pereira, Cathrine Petersen, Alexander J. Ehrenberg, Rana A. Eser, Andrew J. Ambrose, Brian Chin, Teddy Yang, Shireen Khan, Raymond Ng, Salvatore Spina, Willian W. Seeley, Bruce L. Miller, Michelle R. Arkin, Lea T. Grinberg |
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| Rok vydání: | 2022 |
| Předmět: |
Aging
Histology Clinical Sciences tau Proteins tau hyperphosphorylation Neurodegenerative caspase-6 Alzheimer's Disease Pathology and Forensic Medicine cell counting tau isoforms Alzheimer Disease Physiology (medical) mental disorders Acquired Cognitive Impairment 2.1 Biological and endogenous factors Humans Aetiology Neurons Neurology & Neurosurgery Caspase 6 tauopathies Prevention Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Brain Brain Disorders Frontotemporal Dementia (FTD) Neurology Tauopathies immunohistochemistry Neurological Dementia Cognitive Sciences Neurology (clinical) tau cleavage |
| Zdroj: | Neuropathology and applied neurobiology, vol 48, iss 5 |
| ISSN: | 1365-2990 |
| Popis: | AimTau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet the relationship between aCasp-6, different forms of tr-tau and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear.MethodsWe generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies.ResultsCasp-6 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies.ConclusionsEarly modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level. |
| Databáze: | OpenAIRE |
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