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

Abstract

Tau, a microtubule-associated protein predominantly localized in neuronal axons, plays a crucial role in promoting microtubule assembly, stabilizing their structure, and participating in axonal transport. Perturbations in tau’s structure and function are implicated in the pathogenesis of neurodegenerative diseases collectively known as tauopathies, the most common disorder of which is Alzheimer’s disease (AD). In tauopathies, it has been found that tau has a variety of post-translational modification (PTM) abnormalities and/or tau is cleaved into a variety of fragments by some specific proteolytic enzymes; however, the precise contributions of these abnormal modifications and fragments to disease onset and progression remain incompletely understood. Herein, we provide an overview about the involvement of distinctive abnormal tau PTMs and different tau fragments in the pathogenesis of AD and other tauopathies and discuss the involvement of proteolytic enzymes such as caspases, calpains, and asparagine endopeptidase in mediating tau cleavage while also addressing the intercellular transmission role played by tau. We anticipate that further exploration into PTMs and fragmented forms of tau will yield valuable insights for diagnostic approaches and therapeutic interventions targeting AD and other related disorders.

Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer’s disease: implications for biomarker development and therapeutic targeting

“…Levels of truncated tau at D314 are elevated in the inferior temporal gyrus of AD and MCI individuals [ 61 ]. Incidentally, caspase-2-cleaved tau fragments have been found in other diseases such as Lewy body disease [ 62 ], and Huntington’s disease [ 63 ], showing that they are not specific to AD or tauopathies [ 64 ].…”

“…Among these strategies, efforts to modulate the impact of caspase-truncated tau are relatively limited. For instance, one approach aims to alleviate the toxicity of truncated tau by inhibiting protease activity or selectively weakening protease-substrate interactions [ 64 ]. An alternative and attractive method centers around inhibiting caspase activation to reduce tau truncation.…”

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

“…PTMs play a central role in a wide range of biological processes, including cell signaling pathway, immune response, DNA damage response, and metabolism ( 3 , 4 ). Dysregulation of PTMs is associated with various diseases, including cancer ( 5 – 7 ), neurodegenerative disorders ( 8 , 9 ), cardiovascular diseases ( 10 ), and metabolic syndromes ( 11 , 12 ). It is critical to explore the regulatory mechanism of PTMs in order to discover the new targets for disease treatments.…”