Dephosphorylation-Targeting Chimeras to Clear Tau Aggregates in Alzheimer's Disease
Researchers here describe an interesting evolution of proteolysis targeting chimera (PROTAC) technology into a form that upregulates the dephosphorylation of tau protein. Tau becomes pathogenic in the aging brain when hyperphosphorylated, and thus reducing it back to its unphosphorylated form should provide benefits to patients in tauopathies such as Alzheimer's disease. The PROTAC style of approach, when applied to this situation, is to produce a molecule capable of binding to phosphorylated tau at one end and a phosphatase at the other. By encouraging phosphatase molecules into close proximity to phosphorylated tau, the pace at which dephosphylation occurs is greatly upregulated.
Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer's disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. Following the development of proteolysis targeting chimeras (PROTACs) for selectively strengthening degradation of protein of interest (POI), a variety of new chimeras, like autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTEC), lysosome-targeting chimeras (LYTACs), antibody-based PROTACs (AbTACs) or proteolysis-targeting antibodies (PROTABs), have been developed. Taking advantage of these technologies, we and others have developed several chimeras for selectively facilitating tau removal in AD and other tauopathies.
Notwithstanding, the general removal of tau protein might be somewhat arbitrary since tau per se plays multifaceted physiological roles in maintaining cell structure and functions. It is the pathological hyperphosphorylation of tau that initiates the formation of neurofibrillary tangles and neurodegeneration in tauopathies. Therefore, specific downregulation of tau phosphorylation might be more refined for the therapy of these diseases. However, direct use of either tau kinase inhibitors or phosphatase activators should take unacceptable toxic side effects, because each of these enzymes concurrently modulates numerous signaling pathways aside from tau.
To achieve better selectivity and inspired by the design of PROTAC-like chimeras, we have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specific suppression of tau hyperphosphorylation. Our DEPTAC consists of the following motifs: (1) a "warhead" specifically recognizing and binding tau (named tau binder, TB), (2) an "anchor" for recruiting phosphatase (named phosphatase recruiter, PPR), (3) an inter-motifs linker, (4) a cell membrane-penetrating sequence, if necessary. Here, we reported the generation and screening principle of DEPTACs and the further verification of their therapeutic effectiveness in cell and animal models of tauopathy.