# Down-Regulation of Acyloxyacyl Hydrolase Expression in Alzheimer’s Disease Impairs LPS Detoxification and Contributes to Brain Pro-Inflammatory Signaling

## TL;DR

This study shows that reduced AOAH enzyme levels in Alzheimer’s brains impair LPS detoxification, contributing to brain inflammation and neurodegeneration.

## Contribution

The first evidence linking AOAH down-regulation via miR-450b-5p to LPS-induced inflammation in Alzheimer’s disease.

## Key findings

- AOAH mRNA levels are reduced in Alzheimer’s brain tissue.
- miR-450b-5p targets AOAH’s 3′-UTR, suppressing its expression.
- AOAH deficiency in HNG cells increases LPS-associated neurotoxicity.

## Abstract

Lipopolysaccharides (LPSs) are potent pro-inflammatory neurotoxins abundant in the gut microbiome and originate primarily from Gram-negative bacteria, such as Escherichia coli. LPS levels increase with brain aging and accumulate around neurons in Alzheimer’s disease (AD) brains. Microbiome-generated LPS and other endotoxins cross gut barriers, enter systemic circulation, and translocate across the blood–brain barrier into vascularized brain regions. These processes are exacerbated by aging and neurovascular diseases. Although pro-homeostatic systems mitigate LPS effects, these defenses can fail. This study provides the first evidence that acyloxyacyl hydrolase (AOAH; EC 3.1.1.77), a microglia-enriched LPS detoxifying enzyme, shows reduced expression in AD brain tissue. Analysis of AD patient brains revealed reduced AOAH messenger RNA (mRNA) levels, accompanied by elevated expression of microRNA (hsa-miR-450b-5p), an inflammation regulator. Furthermore, luciferase reporter assays demonstrated that miR-450b-5p specifically targets the AOAH 3′-UTR, leading to a dose-dependent suppression of reporter activity. Also, in vitro experiments on human neuronal glial (HNG) cells further confirmed down-regulation of AOAH expression at protein levels by miR-450b-5p. These findings suggest miR-450b-5p-mediated AOAH deficiency drives LPS-associated neurotoxicity and inflammatory neurodegeneration in AD.