Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy

Abstract

Synaptic and cognitive deficits mediated by a severe reduction in excitatory neurotransmission caused by a disproportionate accumulation of the neuronal protein tau in dendritic spines is a fundamental mechanism that has been found repeatedly in models of tauopathies, including Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, and traumatic brain injury. Synapses thus damaged may contribute to dementia, among the most feared cause of debilitation in the elderly, and currently there are no treatments to repair them. Caspase-2 (Casp2) is an essential component of this pathological cascade. Although it is believed that Casp2 exerts its effects by hydrolyzing tau at aspartate-314, forming Δtau314, it is also possible that a noncatalytic mechanism is involved because catalytically dead Casp2 is biologically active in at least one relevant cellular pathway, that is, autophagy. To decipher whether the pathological effects of Casp2 on synaptic function are due to its catalytic or noncatalytic properties, we discovered and characterized a new Casp2 inhibitor, compound 1 [pK i (Casp2) = 8.12], which is 123-fold selective versus Casp3 and >2000-fold selective versus Casp1, Casp6, Casp7, and Casp9. In an in vitro assay based on Casp2-mediated cleavage of tau, compound 1 blocked the production of Δtau314. Importantly, compound 1 prevented tau from accumulating excessively in dendritic spines and rescued excitatory neurotransmission in cultured primary rat hippocampal neurons expressing the P301S tau variant linked to FTDP-17, a familial tauopathy. These results support the further development of small-molecule Casp2 inhibitors to treat synaptic deficits in tauopathies.

Complicated Role of Post-translational Modification and Protease-Cleaved Fragments of Tau in Alzheimer’s Disease and Other Tauopathies

“…Δtau314 protein has now been found to have a distribution in the human striatum and prefrontal cortex [ 164 ] and has also been found to be present in the inferior temporal gyrus [ 165 ]. Using caspase-2 inhibitors could block the production of Δtau314, inhibiting the excessive dendritic spinal accumulation of tau and thus influencing excitatory neurotransmission in reverse in cultured primary hippocampal neurons of rats [ 166 ]. Another treatment for this target is the D314E mutation.…”

Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities

“…HJ8.5, a monoclonal antibody recognizing the N-terminal region of tau, is able to effectively in vitro block its seeding capacity and reduce pathological tau aggregates accumulation, microglial activation, and brain atrophy in six-month-old P301S tau transgenic mice, thereby improving their motor/sensorymotor and cognitive deficits [101,102] . 12A12, which selectively binds the pathologically relevant neurotoxic tau26-230 fragment of tau rather than reacting with its physiological form, is able to ameliorate the cognitive decline and memory impairment in Tg2576 and 3xTg mice [103] . Small molecule inhibitors targeting caspase-2 markedly blocked tau cleavage at the Asp314 site, prevented excessive accumulation of toxic tau fragments in dendritic spines, and restored excitatory neurotransmission in primary rat hippocampal neurons expressing the P301S tau variant [104] .…”

Caspase-2 in liver disease and hepatocellular carcinoma

“…These data contribute to understanding the poor performance of Emricasan observed in preclinical and clinical trials in liver disease. Interestingly, new caspase-2 inhibitors have been recently developed with the aim of improving colon cancer therapy [33], as well as for the treatment of neurodegenerative diseases [112,113].…”