Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity

Opland, Carli K.; Bryan, Miles R.; Harris, Braxton; McGillion-Moore, Jake; Tian, Xu; Chen, Youjun; Itano, Michelle S.; Diering, Graham H.; Meeker, Rick B.; Cohen, Todd J.

doi:10.1016/j.isci.2023.106905

Cited by 3 publications

(2 citation statements)

References 103 publications

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“…Nevertheless, tauopathies exhibit pathological tau inclusions with post-translational modifications (PTMs) beyond phosphorylation. Caspase-cleaved tau is highly neurotoxic [ 4 ], and it is present in AD and other tauopathies. Tau protein can undergo cleavage by various caspases, including caspases 1, 2, 3, 6, 7, and 8.…”

Section: Introductionmentioning

confidence: 99%

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

Rizzi,

Grinberg

2024

acta neuropathol commun

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Tauopathies are neurodegenerative diseases that typically require postmortem examination for a definitive diagnosis. Detecting neurotoxic tau fragments in cerebrospinal fluid (CSF) and serum provides an opportunity for in vivo diagnosis and disease monitoring. Current assays primarily focus on total tau or phospho-tau, overlooking other post-translational modifications (PTMs). Caspase-cleaved tau is a significant component of AD neuropathological lesions, and experimental studies confirm the high neurotoxicity of these tau species. Recent evidence indicates that certain caspase-cleaved tau species, such as D13 and D402, are abundant in AD brain neurons and only show a modest degree of co-occurrence with phospho-tau, meaning caspase-truncated tau pathology is partially distinct and complementary to phospho-tau pathology. Furthermore, these caspase-cleaved tau species are nearly absent in 4-repeat tauopathies. In this review, we will discuss the significance of caspase-cleaved tau in the development of tauopathies, specifically emphasizing its role in AD. In addition, we will explore the potential of caspase-cleaved tau as a biomarker and the advantages for drug development targeting caspase-6. Developing specific and sensitive assays for caspase-cleaved tau in biofluids holds promise for improving the diagnosis and monitoring of tauopathies, providing valuable insights into disease progression and treatment efficacy.

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Section: Introductionmentioning

confidence: 99%

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

Rizzi,

Grinberg

2024

acta neuropathol commun

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“…TauΔD421 impairs neuronal firing, causing inefficient initiation of network bursts, consistent with reduced excitatory drive. Since reduced neuronal activity is coupled to proteasome dysfunction, it drives cleaved tau accumulation at the post synaptic density and subsequent synaptotoxicity [ 162 ].…”

Section: Role Of Tau Fragments In Neurodegenerationmentioning

confidence: 99%

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

Yang,

Shen,

Shen

et al. 2023

Mol Neurobiol

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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.

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Cellular stress management by caspases

Baena-Lopez,

Wang,

Wendler

2024

Current Opinion in Cell Biology

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Activity-dependent tau cleavage by caspase-3 promotes neuronal dysfunction and synaptotoxicity

Cited by 3 publications

References 103 publications

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

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

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

Cellular stress management by caspases

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