Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits

Abstract

Active Caspase-6 (Casp6) and Tau cleaved by Casp6 at amino acids 402 (Tau∆D402) and 421 (Tau∆D421) are present in early Alzheimer disease intraneuronal neurofibrillary tangles, which are made primarily of filamentous Tau aggregates. To assess whether Casp6 cleavage of Tau contributes to Tau pathology and Casp6-mediated age-dependent cognitive impairment, we generated transgenic knock-in mouse models that conditionally express full-length human Tau (hTau) 0N4R only (CTO) or together with human Casp6 (hCasp6) (CTC). Region-specific hippocampal and cortical hCasp6 and hTau expression were confirmed with western blot and immunohistochemistry in 2–25-month-old brains. Casp6 activity was confirmed with Tau∆D421 and Tubulin cleaved by Casp6 immunopositivity in 3–25-month-old CTC, but not in CTO, brains. Immunoprecipitated Tau∆D402 was detected in both CTC and CTO brains, but was more abundant in CTC brains. Intraneuronal hippocampal Tau hyperphosphorylation at S202/T205, S422, and T231, and Tau conformational change were absent in both CTC and CTO brains. A slight accumulation of Tau phosphorylated at S396/404 and S202 was observed in Cornu Ammonis 1 (CA1) hippocampal neuron soma of CTC compared to CTO brains. Eighteen-month-old CTC brains showed rare argentophilic deposits that increased by 25 months, whereas CTO brains only displayed them sparsely at 25 months. Tau microtubule binding was equivalent in CTC and CTO hippocampi. Episodic and spatial memory measured with novel object recognition and Barnes maze, respectively, remained normal in 3–25-month-old CTC and CTO mice, in contrast to previously observed impairments in ACL mice expressing equivalent levels of hCasp6 only. Consistently, the CTC and CTO hippocampal CA1 region displayed equivalent dendritic spine density and no glial inflammation. Together, these results reveal that active hCasp6 co-expression with hTau generates Tau cleavage and rare age-dependent argentophilic deposits but fails to induce cognitive deficits, neuroinflammation, and Tau pathology.

NLRP1 Inflammasome Activation in the Hippocampal Formation in Alzheimer’s Disease: Correlation with Neuropathological Changes and Unbiasedly Estimated Neuronal Loss

“…Active CASP-6 immunostaining is the strongest of all markers analyzed in this study, and it is higher in the AD group compared to HC, in line with previous studies of AD brain tissues [ 23 , 25 , 26 , 71 , 73 , 74 , 75 ]. We show that neuronal CASP-6 immunoreactivity in the hippocampal formation positively correlates with the immunostaining for NLRP1 and ASC, which is congruent with its cleavage downstream of NLRP1 inflammasome activation in neurons [ 23 ].…”

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

“…I n vitro , caspase-3-cleaved tau at Asp421 assembles into filaments more rapidly than wild-type tau [ 28 ]. TauC3 may contribute to the propagation of tau pathology by inducing mitochondrial fragmentation and bioenergetics dysfunction in neuronal cells [ 25 , 34 , 35 ], neurite loss in neuronal cultures, and increasing tau polymerization and aggregation in vitro [ 28 , 36 ]. In vivo, multiphoton imaging in a living tau transgenic mice model (Tg4510 strain), de Calignon et al detected tau D421, generated by caspase-3-cleavage preceding neurofibrillary tangle pathology and determined that tau D421 promoted the formation of neurofibrillary tangles [ 37 , 38 ].…”

Cell Death Related Proteins Beyond Apoptosis in the CNS

“…Early studies described caspase-6 as capable of processing tau (Horowitz et al, 2004;Rissman et al, 2004). However, in hippocampal and cortical neurons tau fragments generated by caspase-6 are insufficient per se to induce tau pathogenesis, as shown recently using a transgenic knock-in mouse model expressing full-length human tau together with human Casp6 (Noël et al, 2021).…”