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

Abstract

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.

• Authors: Ahmed Morsy, Paul C Trippier
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 9 Pg. 4252-4264 (05 09 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 30444369 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

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

Topics

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