Genetic deletion of TRPA1 receptor attenuates amyloid beta- 1-42 (Aβ1-42)-induced neurotoxicity in the mouse basal forebrain in vivo

M Payrits,E Borbely,S Godo,D Ernszt,A Kemeny,J Kardos,E Szoke,E Pinter

doi:10.1016/j.mad.2020.111268

Abstract

Amyloid β 1–42 peptide (Aβ1–42) accumulates in Alzheimer's disease (AD) that is toxic to the basal forebrain cholinergic (BFC) neurons in substantia innominata-nucleus basalis magnocellularis complex (SI-NBM). Transient Receptor Potential Ankyrin1 (TRPA1) receptor is present in murine brain, however its role in neurotoxic processes is unclear. We investigated the Aβ1–42-induced neurotoxicity in TRPA1 wild-type (TRPA1+/+) and knockout (TRPA1−/−) mice.Expression and neuroanatomical localization of TRPA1 receptor were examined using RT qPCR. Cholinergic fibre loss was determined on acetylcholinesterase (AChE) stained brain slices, and choline acetyltransferase (ChAT) immunohistochemistry was used to assess the cholinergic cell loss. Novel object recognition (NOR), radial arm maze (RAM) and Y-maze tests were used to investigate memory loss.Aβ1–42-injected WT mice showed marked loss of cholinergic fibres and cell bodies, which was significantly attenuated in TRPA1−/− animals. According to the NOR and RAM tests, pronounced memory loss was detected in Aβ1–42-injected TRPA1+/+ mice, but not in TRPA1−/− group.Our findings demonstrate that TRPA1 KO animals show substantially reduced morphological damage and memory loss after Aβ1–42 injection in the SI-NBM. We conclude that TRPA1 receptors may play an important deteriorating role in the Aβ1–42-induced cholinergic neurotoxicity and the consequent memory loss in the murine brain.

Highlights

One of the major pathomorphological hallmarks of Alzheimer’s disease (AD) is the significant neuronal death in the cortex, hippocampus and basal forebrain
Our findings demonstrate that transient receptor potential ankyrin 1 (TRPA1) KO animals show substantially reduced morphological damage and memory loss after Amyloid β 1–42 peptide (Aβ1–42) injection in the substantia innominata-nucleus basalis magnocellularis complex (SI-nucleus basalis magnocellularis (NBM))
To elucidate whether Trpa1 is expressed in brain regions relevant to this work, we performed RT-qPCR in micropunched areas obtained from TRPA1+/+ or TRPA1−/− animals

Summary

Introduction

One of the major pathomorphological hallmarks of Alzheimer’s disease (AD) is the significant neuronal death in the cortex, hippocampus and basal forebrain. The Aβ activates astrocytes and microglial cells, it has direct neurotoxic effect by ligand-like interaction with the N-methyl-D-aspartate (NMDA) glutamate receptors (Harkany et al, 2000). There is an increasing evidence that neuro-immune interactions may play a critical role in the pathomechanism of several neurodegenerative diseases (Candore et al, 2007; Masters et al, 2015, Sághy et al, 2016) and regulatory role of the transient receptor potential (TRP) ion channels is strongly suggested in these processes. TRP channels are sensitive for various stimuli including mechanical, thermal triggers or chemical ligands. Considering these interactions, they are likely to be sensors for several physiological or pathophysiological stimuli (Khalil et al, 2018). The principal aims of the present study were to investigate the morphological and the functional aspects of TRPA1-mediated events in BFC using Aβ1–42-induced neurotoxicity model in TRPA1 knockout mice

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