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

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 (ADLP APT ) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patientderived 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 ADLP APT mice.

Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer’s disease

“…HDAC6 levels are elevated in AD and may be involved in the degradation of tau based on HDAC6 involvement in the ubiquitin-proteasome system and autophagy pathway [50]. As expected, decreased levels of acetylated α-tubulin and elevated levels of HDAC6 were observed in AD-like COs with pathological tau aggregates compared to control COs [49]. CKD-504, a blood-brain barrier (BBB) penetrating HDAC6 inhibitor, was tested on COs generated from hiPSCs with FAD variants.…”

“…COs have also been used to explore post-translational modifications that may affect the interaction of tau with the molecular chaperones that are responsible for its degradation [49]. For instance, histone deacetylase 6 (HDAC6) is responsible for the deacetylation of α-tubulin and tau [50].…”

Retinal and Brain Organoids: Bridging the Gap Between in vivo Physiology and in vitro Micro-Physiology for the Study of Alzheimer’s Diseases

“…partially inhibit the production of toxic Aβ and to reduce the hyperphosphorylation of tau proteins, suggesting the Aβ-driven tauopathy theory (Lee et al, 2016;Raja et al, 2016). Mook-Jung and collaborators reported the discovery of CDK-504 (Choi et al, 2020), a selective histone-deacetylase 6 inhibitor, which dramatically enhances the proteasome degradation pathway of pathological tau in AD patient-derived brain organoids and rescues synaptic deficits. The use of brain organoids can also accelerate Aβ accumulation in culture, thus facilitating the characterization of the associated cellular and molecular events (Raja et al, 2016).…”

Acetylation stabilizes chloride intracellular channel 1 that exerts a tumor-promoting role by activation of nuclear factor kappa B in cervical cancer

“…Lysine acetylation is a common posttranslational modification (PTM) regulating protein stability, subcellular localization, and function [17]. Acetylation of histone and nonhistone was reported to be involved in many diseases, including aging-associated chronic inflammation and insulin resistance [18], cancer [19][20][21], colitis [22], and Alzheimer's disease [23]. In previous work, we analyzed the lysine acetylproteome in three primary cervical cancer tissues and corresponding adjacent normal tissues by using the label-free proteomics approach and found that acetylation levels of CLIC1 at lysine 131 were significantly increased in tumor tissues.…”