Research Paper Volume 14, Issue 20 pp 8221—8242
AR12 increases BAG3 expression which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy
- 1 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA
- 2 Department of Surgery, Virginia Commonwealth University, Richmond, VA 23298, USA
- 3 Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA
- 4 National Institute of Environmental Health Sciences, Inflammation and Autoimmunity Group, Triangle Park, Durham, NC 27709, USA
- 5 Translational Genomics Research Institute (TGen), Phoenix, AZ 85004, USA
- 6 Banner Alzheimer’s Institute, Phoenix, AZ 85006, USA
Received: August 17, 2022 Accepted: October 5, 2022 Published: October 13, 2022
https://doi.org/10.18632/aging.204337How to Cite
Copyright: © 2022 Dent et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
We defined the mechanisms by which the chaperone ATPase inhibitor AR12 and the multi-kinase inhibitor neratinib interacted to reduce expression of Tau and amyloid-precursor protein (APP) in microglia and neuronal cells. AR12 and neratinib interacted to increase the phosphorylation of eIF2A S51 and the expression of BAG3, Beclin1 and ATG5, and in parallel, enhanced autophagosome formation and autophagic flux. Knock down of BAG3, Beclin1 or ATG5 abolished autophagosome formation and significantly reduced degradation of p62, LAMP2, Tau, APP, and GRP78 (total and plasma membrane). Knock down of Rubicon, a key component of LC3-associated phagocytosis (LAP), significantly reduced autophagosome formation but not autophagic flux and prevented degradation of Tau, APP, and cell surface GRP78, but not ER-localized GRP78. Knock down of Beclin1, ATG5 or Rubicon or over-expression of GRP78 prevented the significant increase in eIF2A phosphorylation. Knock down of eIF2A prevented the increase in BAG3 expression and significantly reduced autophagosome formation, autophagic flux, and it prevented Tau and APP degradation. We conclude that AR12 has the potential to reduce Tau and APP levels in neurons and microglia via the actions of LAP, endoplasmic reticulum stress signaling and macroautophagy. We hypothesize that the initial inactivation of GRP78 catalytic function by AR12 facilitates an initial increase in eIF2A phosphorylation which in turn is essential for greater levels of eIF2A phosphorylation, greater levels of BAG3 and macroautophagy and eventually leading to significant amounts of APP/Tau degradation.
Abbreviations
APP: amyloid precursor protein; ER: endoplasmic reticulum; AIF: apoptosis inducing factor; AMPK: AMP-dependent protein kinase; mTOR: mammalian target of rapamycin; MAPK: mitogen activated protein kinase; CMV: empty vector plasmid or virus; si: small interfering; SCR: scrambled; VEH: vehicle; NER: neratinib; AD: Alzheimer’s Disease; LAP: LC3-associated phagocytosis; mTOR: mammalian target of rapamycin.