# Cholinergic Transmission Dysregulation and Neurodegeneration Induced by Thyroid Signaling Disruption Following Butylparaben Single and Repeated Treatment

## TL;DR

This study shows how butylparaben, a common preservative, may cause brain cell damage and cognitive issues by disrupting thyroid signaling and cholinergic pathways.

## Contribution

The study reveals novel mechanistic links between butylparaben exposure and neurodegeneration via thyroid hormone disruption and oxidative stress.

## Key findings

- Butylparaben disrupts cholinergic transmission by inhibiting acetylcholinesterase and inducing oxidative stress.
- BP causes cell death through thyroid hormone pathway disruption and accumulation of Aβ and p-Tau proteins.
- Oxidative stress and NRF2 pathway disruption mediate butylparaben-induced neurodegeneration.

## Abstract

Environmental pollutants have been implicated as potential contributors to the development of Alzheimer’s disease (AD) and other neurodegenerative disorders. Among these is the widely used preservative butylparaben, which has been shown to cause neurodegeneration and cognitive deficits similar to those observed in AD. However, the precise mechanisms by which butylparaben and other environmental pollutants exert these effects remain unknown. In AD and related dementias, a selective loss of cholinergic neurons occurs in the basal forebrain. This loss leads to the denervation of key projection areas like the hippocampus and cortex, resulting in neurodegeneration in these regions and, ultimately, cognitive impairment. Our results identify alterations in specific mechanisms that may mediate butylparaben’s disruption of cholinergic transmission and its role in inducing the degeneration of basal forebrain cholinergic neurons. These findings could help explain the mechanisms behind the cognitive alterations induced by butylparaben and other pollutants that operate similarly. Ultimately, this understanding may pave the way for developing preventive and therapeutic strategies to mitigate these effects in the population.

Butylparaben (BP), a widely used preservative, was implicated in cognitive impairment, though its neurotoxic mechanisms remain elusive. Basal forebrain cholinergic neurons (BFCN) are selectively lost in dementias, contributing to cognitive decline. To explore different mechanisms related with BFCN loss, we employed BF SN56 cholinergic wild-type or silenced cells for Tau, amyloid-beta precursor protein (βApp), acetylcholinesterase (AChE), or glycogen synthase kinase-3 beta (GSK3β) genes, exposing them to BP (0.1–80 µM) for 1 or 14 days alongside triiodothyronine (T3; 15 nM), N-acetylcysteine (NAC; 1 mM), or recombinant heat shock protein 70 (rHSP70; 30 µM). BP disrupted cholinergic transmission by AChE inhibition and provoked cell death through thyroid hormones (THs) pathway disruption, Aβ/p-Tau protein accumulation, AChE-S overexpression, and oxidative stress (OS). Aβ/p-Tau accumulation was correlated with HSP70 downregulation, OS exacerbation, and GSK3β hyperactivation (for p-Tau). BP-induced OS was mediated by reactive oxygen species (ROS) overproduction and nuclear factor erythroid 2-related factor 2 (NRF2) pathway disruption. All observed effects were contingent upon TH signaling impairment. These findings uncover novel mechanistic links between BP exposure and BFCN neurodegeneration, providing a framework for therapeutic strategies.