Caspase‐6‐cleaved tau is relevant in Alzheimer's disease and marginal in four‐repeat tauopathies: Diagnostic and therapeutic implications

Year: 2022

Type: article

Abstract: Aim Tau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. 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. Methods We generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used 5-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. Results Casp-6 activation was strongest in AD, followed by Pick’s disease (PiD), but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD than in 4R tauopathies, and disproportionally higher when normalizing 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 lacked p-tau aggregates. Conclusions Early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD, and possibly PiD, but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that not all neurons that are vulnerable to tau pathology are detected by a conventional p-tau Ser 202 antibody and that AD has distinct mechanisms of tangle formation. Therapeutic strategies against tr-tau pathology could be necessary to modulate tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD supports the investigation of biofluid biomarkers against N-terminus tr-tau, which could detect AD and differentiate it from 4R tauopathies at a single patient level. 3 - sentence summary Tau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation, but the relationship between aCasp-6, tr-tau, and hyperphosphorylated tau (p-tau) accumulation in Alzheimer’s disease (AD) and other tauopathies remains unclear. We generated two neoepitope monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6 and used 5-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau, and their co-occurrence in brains from healthy controls, AD, and primary tauopathies. We detected relatively high Casp-6 activation in AD, followed by Pick’s disease (PiD). aCasp-6 was almost absent in 4-repeat (4R) tauopathies, suggesting that early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy in AD, and possibly PiD, but is unlikely to benefit 4R tauopathies.

Source: Neuropathology and Applied Neurobiology

DOI: 10.1111/nan.12819

Authors: 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

Institutions: University of California, San Francisco, UCSF Edward and Pearl Fein Memory and Aging Center, Global Brain Health Institute, Universidade de São Paulo

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Alzheimer's Association, Rainwater Charitable Foundation, National Institutes of Health, University of California, San Francisco, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke

OpenAlex ID: W4229033918