Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease

J Med Chem. 2019 May 9;62(9):4252-4264. doi: 10.1021/acs.jmedchem.8b01530. Epub 2018 Nov 30.


Alzheimer's disease (AD) is the most common dementia. No cure exists, and current treatment only manages early symptoms. Mitochondrial dysfunction is a hallmark of amyloid-β (Aβ) neurotoxicity, the pathogenic protein implicated in AD. This is due in part to the interaction between Aβ and amyloid-binding alcohol dehydrogenase (ABAD). This mitochondrial protein is a vital energy regulator that, following Aβ binding, activates signaling cascades that lead to neuronal death. One of the most significant roles of ABAD is to maintain the balance of estradiol/estrone in neurons. However, the Aβ-ABAD interaction disrupts this balance and leads to a reduction in levels of estradiol, thus leading to an increase in reactive oxygen species levels and to apoptosis. Two additional proteins, peroxiredoxin-2 and endophilin-1, are implicated in Aβ-ABAD complex-mediated toxicity. Targeting the Aβ-ABAD interaction has emerged as a novel therapeutic strategy for AD. Herein, we review the chemistry and pharmacology of reported ABAD inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 3-Hydroxyacyl CoA Dehydrogenases / antagonists & inhibitors*
  • 3-Hydroxyacyl CoA Dehydrogenases / metabolism*
  • Acyltransferases / metabolism
  • Alzheimer Disease / drug therapy*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Mitochondria / metabolism
  • Peroxiredoxins / metabolism
  • Protein Binding / drug effects*


  • Amyloid beta-Peptides
  • Enzyme Inhibitors
  • 3-Hydroxyacyl CoA Dehydrogenases
  • HSD17B10 protein, human
  • PRDX2 protein, human
  • Peroxiredoxins
  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase