Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias

Abstract

Targeting amyloid-β plaques and tau tangles has failed to provide effective treatments for Alzheimer's disease and related dementias (ADRD). A more fruitful pathway to ADRD therapeutics may be the development of therapies that target common signaling pathways that disrupt synaptic connections and impede communication between neurons. In this review, we present our characterization of a signaling pathway common to several neurological diseases featuring dementia including Alzheimer's disease, frontotemporal dementia, Lewy body dementia, and Huntington's disease. This signaling pathway features the cleavage of tau by caspase-2 (Casp2) yielding Δtau314 (Casp2/tau/Δtau314). Through a not yet fully delineated mechanism, Δtau314 catalyzes the mislocalization and accumulation of tau to dendritic spines leading to the internalization of AMPA receptors and the concomitant weakening of synaptic transmission. Here, we review the accumulated evidence supporting Casp2 as a druggable target and its importance in ADRD. Additionally, we provide a brief overview of our initial medicinal chemistry explorations aimed at the preparation of novel, brain penetrant Casp2 inhibitors. We anticipate that this review will spark broader interest in Casp2 as a target for restoring synaptic dysfunction in ADRD.

Figure 1.

Sites in 2N/4R tau that have been observed to be cleaved by caspases. These results are typically observed in in vitro experiments with recombinant tau.^, (1) Asp421: cleavage site for Casp1, Casp2, Casp3, Casp6, Casp7, and Casp8. Cleavage here leads to fibrillar tau filaments and to tangles. This is a canonical cleavage site (D-aa-aa-D, where aa = amino acid) for Casp2, 3, 7, 8 and a non-canonical cleavage site for Casp1. Casp2 cleaves tau at this site only in vitro. (2) Asp314: Casp2 cleavage site. Cleavage here results in the formation of Δtau314, a non-fibrillar form of tau. This is a non-canonical cleavage site. Casp2 cleaves tau at this site in vitro and in vivo. (3) Caspase cleavage sites in the N-terminal region of tau. Asp13: cleavage site for Casp6 (canonical). Asp25: cleavage site for Casp3 (canonical). (4) Although this is a canonical cleavage site for Casp2, 3, 7, 8, no cleavage at this site has been observed. Tau image based on Xia et al. Created with BioRender.com.

Figure 2.

The current mechanistic understanding of the roles of Casp2 and tau in synaptic function. (1) Tau undergoes post-translational modification (PTM) and is released from microtubules. (2) PTM-tau is cleaved by active Casp2 to yield Δtau314. (3) Δtau314 catalyzes the movement of tau from the neuron into the dendrite thereby positively regulating calcineurin activity, (4) which in turn causes reversible internalization of AMPAR at the synapse. Under normal physiological conditions, neural signals regulate Casp2 activity leading to long-term depression (LTD). However, under pathological conditions various forms of cellular stress abnormally activate Casp2 independent of the neural signals leading to a dysfunctional, sustained LTD-like state that depresses excitatory neurotransmission. (5) Other proteases cleave tau leading to fragments with distinct mechanism of action. Created with BioRender.com.

Figure 3.

The Casp2/tau/Δtau314 cascade of events we propose to be involved in dementia. Cellular stress (typically in the form of ER stress, reactive oxygen, DNA damage, tau mutants such as tauP301L, etc.) activates Casp2, which in turn increases levels of Δtau314. This leads to the internalization of AMPAR, synaptic weakening and, ultimately, forgetfulness and dementia in multiple neurodegenerative conditions. The successful development of drugs that inhibit Casp2 could halt this insidious cascade of events and restore cognition. Created with BioRender.com.

Figure 4.

Structures of selective Casp2 inhibitors S-33q, compound 1, and compound 3, and the caspase prodrugs VX-765 (Casp1 inhibitor) and TRP601 (Casp2/3 inhibitor).

Figure 5.

The computationally predicted (CovDock, Schrödinger)^, binding of compound 1 with the Casp2 apo-structure (ligand removed) from PDB:1PYO. Important interactions that confer selectivity are shown: the P5 indoline amide interaction with the amide of Y273; the P2 4-methyltetrahydroisoquinoline interaction with the S2 subpocket. (For further details on the computational methods see Bresinsky et al.).