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

Abstract

Aim: Tau 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.Methods: We 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 cooccurrence in healthy controls, AD and primary tauopathies.Results: Casp-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.Conclusions: Early 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

Engaging a Non-catalytic Cysteine Residue Drives Potent and Selective Inhibition of Caspase-6

“…While often classified as an executioner caspase, the function of caspase-6 (C6) in physiology and disease has remained enigmatic, and it has been suggested that C6 may act upstream of the other executioner caspases. , In addition to a putative amplifying role during apoptosis, C6 has been found to also possess nonapoptotic functions important for axon pruning and neuroinflammation. − Finally, C6-mediated proteolysis has been implicated in the pathology of Huntington’s , and Alzheimer’s disease, − in neuroinflammation generally − and in nonalcoholic steatohepatitis …”

Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer’s disease: implications for biomarker development and therapeutic targeting

“…Caspase-6- cleavage of tau at Asp402 generates a 1-402 fragment, associated with neurodegeneration, and the 403–441 with unknown functions [ 52 ]. Altogether, both active caspase-6 and tau truncated at Asp402 and Asp13 are present in neurofibrillary tangles, neuritic plaques, and neuropil threads in sporadic and familial AD but absent in brains without AD pathology [ 7 , 23 , 48 , 53 ].…”

“…Limited studies on cerebrospinal fluid (CSF) involving caspase-cleaved tau indicate that these fragments are released and can be identified in the CSF, potentially exhibiting a meaningful correlation with clinical deterioration [ 5 , 6 ]. Recent findings indicate that caspase-6 cleaved tau D13 and D402, commonly present in AD neurons, but rarely in 4-repeat tauopathies, only partially overlap with phospho-tau in the same neuron [ 7 ]. This implies that caspase-cleaved tau can signal tau pathology distinct from phospho-tau, highlighting a pathway that cannot be identified solely through phospho-tau-based biomarkers.…”

Disruption of protein geranylgeranylation in the cerebellum causes cerebellar hypoplasia and ataxia via blocking granule cell progenitor proliferation

“…Whereas Alzheimer's disease (AD), PD, multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are well-known neurological disorders [22][23][24][25], abnormal protein prenylation has been widely observed in patients with these diseases [26][27][28][29][30]. Recent evidence has shown that protein prenylation may be important for synaptic plasticity in the hippocampus and dendritic morphogenesis in the cortex [31,32].…”