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Aging Cell. 2019 Nov 25:e13081. doi: 10.1111/acel.13081. [Epub ahead of print]

Acetylation changes tau interactome to degrade tau in Alzheimer's disease animal and organoid models.

Author information

1
Department of Biochemistry and Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.
2
Department of Pharmacology, CKD Research Institute, CKD Pharmaceutical Company, Seoul, Korea.
3
Center for Plant Aging Research, Institute for Basic Science, DGIST, Daegu, Korea.
4
Korea Brain Bank, Korea Brain Research Institute, Daegu, Korea.
5
Interdisciplinary Graduate Program in Genetic Engineering, Seoul National University, Seoul, Korea.
6
Department of Medicinal Chemistry, CKD Research Institute, CKD Pharmaceutical Company, Seoul, Korea.
7
Department of Nonclinical Development, CKD Research Institute, CKD Pharmaceutical Company, Seoul, Korea.
8
Department of New Biology, DGIST, Daegu, Korea.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD-504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT ) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient-derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau-interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice.

KEYWORDS:

Alzheimer's disease; neurodegenerative diseases; tau; tau interactome; tau post-translational modification

PMID:
31763743
DOI:
10.1111/acel.13081
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