ACAT1 as a Therapeutic Target and its Genetic Relationship with Alzheimer's Disease

Abstract

Background: Alzheimer´s disease (AD) is a chronic and progressive disease which impacts caregivers, families and societies physically, psychologically and economically. Currently available drugs can only improve cognitive symptoms, have no impact on progression and are not curative, so identifying and studying new drug targets is important. There are evidences which indicate disturbances in cholesterol homeostasis can be related with AD pathology, especially the compartmentation of intracellular cholesterol and cytoplasmic cholesterol esters formed by acyl-CoA: cholesterol acyltransferase 1 (ACAT1) can be implicated in the regulation of amyloid-beta (Aβ) peptide, involved in AD. Blocking ACAT1 activity, beneficial effects are obtained, so it has been suggested that ACAT1 can be a potential new therapeutic target. The present review discusses the role of cholesterol homeostasis in AD pathology, especially with ACAT inhibitors, and how they have been raised as a therapeutic approach. In addition, the genetic relationship of ACAT and AD is discussed. Conclusion: Although there are several lines of evidence from cell-based and animal studies that suggest that ACAT inhibition is an effective way of reducing cerebral Aβ, there is still an information gap in terms of mechanisms and concerns to cover before passing to the next level. Additionally, an area of interest that may be useful in understanding AD to subsequently propose new therapeutic approaches is pharmacogenetics; however, there is still a lot of missing information in this area.

27-Hydroxycholesterol-Induced Dysregulation of Cholesterol Metabolism Impairs Learning and Memory Ability in ApoE ε4 Transgenic Mice

“…This is consistent with the finding that three transgenic familial AD mice had increased cholesterol esters [ 58 ]. ACAT1 inhibition reduces cerebral Aβ [ 59 ]. These findings support our hypothesis that 27-OHC regulates cognitive function by altering cholesterol esterification.…”

Genetic underpinnings of affective temperaments: a pilot GWAS investigation identifies a new genome-wide significant SNP for anxious temperament in ADGRB3 gene

“…Furthermore, functional prediction analyses implicated top SNPs for the anxious temperament to be associated with the expression of various genes in the central nervous system in areas relevant both for emotional reactivity and affective illnesses, such as SLC35F2 in the DLPFC, hypothalamus and nucleus accumbens, and implicated in GWASs for unipolar depression, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder 53 . Top SNPs for the anxious temperament also influence expression of ACAT1 encoding the acetyl-CoA Acetyltransferase1, the major isoform in the brain, which has been implicated in several neurodegenerative disorders and has recently emerged as a promising target in the treatment of Alzheimer’s disease 54 and glioblastoma 55 . Top SNPs for the anxious temperament also regulate the expression of ELMOD1 , which has previously been associated with personality 56 and delayed discounting measures 57 .…”