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Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy. 2022

Gurpreet Singh, and Peng Liu, and Katherine R Yao, and Jessica M Strasser, and Chris Hlynialuk, and Kailee Leinonen-Wright, and Peter J Teravskis, and Jessica M Choquette, and Junaid Ikramuddin, and Merlin Bresinsky, and Kathryn M Nelson, and Dezhi Liao, and Karen H Ashe, and Michael A Walters, and Steffen Pockes
Department of Medicinal Chemistry, The University of Minnesota, Minneapolis, Minnesota 55455, United States.

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 [pKi (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.

UI MeSH Term Description Entries
D008822 Mice, Transgenic Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN. Transgenic Mice,Founder Mice, Transgenic,Mouse, Founder, Transgenic,Mouse, Transgenic,Mice, Transgenic Founder,Transgenic Founder Mice,Transgenic Mouse
D009435 Synaptic Transmission The communication from a NEURON to a target (neuron, muscle, or secretory cell) across a SYNAPSE. In chemical synaptic transmission, the presynaptic neuron releases a NEUROTRANSMITTER that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across ELECTRICAL SYNAPSES. Neural Transmission,Neurotransmission,Transmission, Neural,Transmission, Synaptic
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D016875 tau Proteins Microtubule-associated proteins that are mainly expressed in neurons. Tau proteins constitute several isoforms and play an important role in the assembly of tubulin monomers into microtubules and in maintaining the cytoskeleton and axonal transport. Aggregation of specific sets of tau proteins in filamentous inclusions is the common feature of intraneuronal and glial fibrillar lesions (NEUROFIBRILLARY TANGLES; NEUROPIL THREADS) in numerous neurodegenerative disorders (ALZHEIMER DISEASE; TAUOPATHIES). tau Protein,Protein, tau,Proteins, tau
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D053143 Caspase 2 A long pro-domain caspase that contains a caspase recruitment domain in its pro-domain region. Activation of this enzyme can occur via the interaction of its caspase recruitment domain with CARD SIGNALING ADAPTOR PROTEINS. Caspase 2 plays a role in APOPTOSIS by cleaving and activating effector pro-caspases. Several isoforms of this protein exist due to multiple alternative splicing of its MESSENGER RNA. Caspase 2 Subunit p12,Caspase 2 Subunit p13,Caspase 2 Subunit p18,Caspase-2,ICH-1 Protease,Pro-Caspase-2,Procaspase-2,ICH 1 Protease,Pro Caspase 2,Procaspase 2
D057180 Frontotemporal Dementia The most common clinical form of FRONTOTEMPORAL LOBAR DEGENERATION, this dementia presents with personality and behavioral changes often associated with disinhibition, apathy, and lack of insight. DDPAC,Dementia, Frontotemporal,Dementia, Frontotemporal, with Parkinsonism,Dementia, Hereditary Dysphasic Disinhibition,Disinhibition-Dementia-Parkinsonism-Amyotrophy Complex,Disinhibition-Dementia-Parkinsonism-Amytrophy Complex,FTD-GRN,FTD-PGRN,FTDP-17,FTLD with TDP-43 Pathology,FTLD-17 GRN,FTLD-TDP,Familial Pick's Disease,Frontotemporal Dementia with Parkinsonism,Frontotemporal Dementia with Parkinsonism-17,Frontotemporal Dementia, Ubiquitin-Positive,Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions,Frontotemporal Lobe Dementia,Frontotemporal Lobe Dementia (FLDEM),GRN-Related Frontotemporal Dementia,HDDD1,HDDD2,Hereditary Dysphasic Disinhibition Dementia,Multiple System Tauopathy with Presenile Dementia,Semantic Dementia,Wilhelmsen-Lynch Disease,Complex, Disinhibition-Dementia-Parkinsonism-Amyotrophy,Complex, Disinhibition-Dementia-Parkinsonism-Amytrophy,Complices, Disinhibition-Dementia-Parkinsonism-Amyotrophy,Complices, Disinhibition-Dementia-Parkinsonism-Amytrophy,Dementia, Frontotemporal Lobe,Dementia, Frontotemporal Lobe (FLDEM),Dementia, GRN-Related Frontotemporal,Dementia, Semantic,Dementia, Ubiquitin-Positive Frontotemporal,Dementias, Frontotemporal,Dementias, Frontotemporal Lobe,Dementias, Frontotemporal Lobe (FLDEM),Dementias, GRN-Related Frontotemporal,Dementias, Semantic,Dementias, Ubiquitin-Positive Frontotemporal,Disease, Familial Pick's,Disease, Wilhelmsen-Lynch,Diseases, Familial Pick's,Diseases, Wilhelmsen-Lynch,Disinhibition Dementia Parkinsonism Amyotrophy Complex,Disinhibition Dementia Parkinsonism Amytrophy Complex,Disinhibition-Dementia-Parkinsonism-Amyotrophy Complices,Disinhibition-Dementia-Parkinsonism-Amytrophy Complices,FTLD with TDP 43 Pathology,Familial Pick Disease,Familial Pick's Diseases,Familial Picks Disease,Frontotemporal Dementia with Parkinsonism 17,Frontotemporal Dementia, GRN-Related,Frontotemporal Dementia, Ubiquitin Positive,Frontotemporal Dementias,Frontotemporal Dementias, GRN-Related,Frontotemporal Dementias, Ubiquitin-Positive,Frontotemporal Lobar Degeneration With Ubiquitin Positive Inclusions,Frontotemporal Lobe Dementias,Frontotemporal Lobe Dementias (FLDEM),GRN Related Frontotemporal Dementia,GRN-Related Frontotemporal Dementias,Lobe Dementia, Frontotemporal,Lobe Dementias, Frontotemporal,Pick's Disease, Familial,Pick's Diseases, Familial,Semantic Dementias,Ubiquitin-Positive Frontotemporal Dementia,Ubiquitin-Positive Frontotemporal Dementias,Wilhelmsen Lynch Disease,Wilhelmsen-Lynch Diseases

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