Tau degradation in Alzheimer's disease: Mechanisms and therapeutic opportunities

Abstract

In Alzheimer's disease (AD), tau undergoes abnormal post-translational modifications and aggregations. Impaired intracellular degradation pathways further exacerbate the accumulation of pathological tau. A new strategy - targeted protein degradation - recently emerged as a modality in drug discovery where bifunctional molecules bring the target protein close to the degradation machinery to promote clearance. Since 2016, this strategy has been applied to tau pathologies and attracted broad interest in academia and the pharmaceutical industry. However, a systematic review of recent studies on tau degradation mechanisms is lacking. Here we review tau degradation mechanisms (the ubiquitin-proteasome system and the autophagy-lysosome pathway), their dysfunction in AD, and tau-targeted degraders, such as proteolysis-targeting chimeras and autophagy-targeting chimeras. We emphasize the need for a continuous exploration of tau degradation mechanisms and provide a future perspective for developing tau-targeted degraders, encouraging researchers to work on new treatment options for AD patients. HIGHLIGHTS: Post-translational modifications, aggregation, and mutations affect tau degradation. A vicious circle exists between impaired degradation pathways and tau pathologies. Ubiquitin plays an important role in complex degradation pathways. Tau-targeted degraders provide promising strategies for novel AD treatment.

Keywords: Alzheimer's disease; autophagy; autophagy‐targeting chimeras (AUTOTACs); degradation; proteolysis‐targeting chimeras (PROTACs); targeted protein degradation; tau; ubiquitin–proteasome system.

FIGURE 1

Tau degradation by ubiquitin proteasome system (UPS). Under normal conditions, tau is degraded by the 20S proteasome. After certain post‐translational modifications (PTMs), tau is ubiquitinated by series E1/E2/E3 ubiquitin (Ub) transfer processes and delivered to the 26S proteasome for proteolysis into short peptides. Tau oligomers and filamentous aggregates can be disaggregated by the chaperone complex (Hsp70‐Hsp110‐JDPs) to monomeric tau. The 26S proteasome can also fragment filamentous aggregates and remove soluble oligomers, which is independent of its peptidase activity. Created with BioRender.com.

FIGURE 2

Tau degradation by the autophagy‐lysosomal pathway (ALP). ALP includes three major types: macroautophagy, chaperone‐mediated autophagy (CMA), and microautophagy. (A) In one of the selective macroautophagy pathways (aggrephagy), ubiquitinated tau is recognized by autophagy cargo receptors, which can bind to LC3 on the phagophore membrane. This leads to the recruitment of tau to phagophores, followed by degradation in the lysosome. (B) In CMA, KFERQ‐like motifs of tau are recognized by the HSC70 chaperone complex, delivered to the lysosomal surface, and internalized into the lysosome through a multimeric complex of lysosome‐associated membrane protein 2A (LAMP2A) for degradation. (C) In selective endosomal microautophagy (eMI), KFERQ‐like motifs of tau are recognized by the HSC70 chaperone complex, which can bind to the endosomal membrane via electrostatic interactions. The late endosomal membrane invaginates and sequesters tau into small microvesicles. Late endosomes can degrade tau directly in the endosomal lumen or upon fusion with autophagosomes/lysosomes. Created with BioRender.com.

FIGURE 3

Schematic of proteolysis‐targeting chimeras (PROTACs), autophagy‐targeting chimeras (AUTOTACs), and RING‐Bait technology. (A) PROTACs bring the target protein close to the E3 ligase, which results in protein ubiquitination, followed by proteasomal degradation. (B) AUTOTACs simultaneously interact with the target protein and the autophagy cargo receptor (eg, p62/SQSTM1), which facilitates p62/SQSTM1 self‐polymerization in complex with target proteins. Then the complex is delivered to the phagophore by binding to LC3, followed by autophagosome formation and lysosomal degradation. (C) RING‐Bait contains a RING domain of the E3 ligase tripartite motif‐containing protein 21 (TRIM21) and a bait, such as the target protein. During the target protein aggregation, RING‐Baits are recruited into the aggregates. This clustering dimerizes the RING domain and activates its E3 function, leading to subsequent proteasomal degradation. Created with BioRender.com.

FIGURE 4

Chemical structures of small‐molecule proteolysis‐targeting chimeras (PROTACs) and autophagy‐targeting chimeras (AUTOTACs) for tau degradation. (A) C8, T3, QC‐01‐175, and I3 are PROTACs with ligands binding to tau and E3 ligase cereblon (CRBN). C004019 is the PROTAC with ligands binding to tau and E3 ligase von Hippel‐Lindau protein (VHL). (B) PBA‐1105, PBA‐1106, and Anle138b‐F105 are AUTOTACs with ligands binding to tau and the autophagy cargo receptor (p62/SQSTM1).