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

Genetic deletion of TRPA1 receptor attenuates amyloid beta- 1-42 (Aβ_1-42)-induced neurotoxicity in the mouse basal forebrain in vivo

Mech Ageing Dev. 2020 Jul:189:111268. doi: 10.1016/j.mad.2020.111268. Epub 2020 May 28.

Authors

M Payrits¹, E Borbely², S Godo³, D Ernszt⁴, A Kemeny⁵, J Kardos⁶, E Szoke⁷, E Pinter⁸

Affiliations

¹ Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; Centre for Neuroscience, Szentágothai Research Center, University of Pécs, Pécs, Hungary. Electronic address: [email protected].
² Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; Centre for Neuroscience, Szentágothai Research Center, University of Pécs, Pécs, Hungary. Electronic address: [email protected].
³ Centre for Neuroscience, Szentágothai Research Center, University of Pécs, Pécs, Hungary; Institute of Physiology, University of Pécs, Pécs, Hungary. Electronic address: [email protected].
⁴ Centre for Neuroscience, Szentágothai Research Center, University of Pécs, Pécs, Hungary; Institute of Physiology, University of Pécs, Pécs, Hungary. Electronic address: [email protected].
⁵ Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; Centre for Neuroscience, Szentágothai Research Center, University of Pécs, Pécs, Hungary; Department of Medical Biology and Central Electron Microscope Laboratory, University of Pécs, Hungary. Electronic address: [email protected].
⁶ ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary. Electronic address: [email protected].
⁷ Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; Centre for Neuroscience, Szentágothai Research Center, University of Pécs, Pécs, Hungary. Electronic address: [email protected].
⁸ Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; Centre for Neuroscience, Szentágothai Research Center, University of Pécs, Pécs, Hungary. Electronic address: [email protected].

PMID: 32473171
DOI: 10.1016/j.mad.2020.111268

Abstract

Amyloid β 1-42 peptide (Aβ_1-42) 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 Aβ_1-42-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. Aβ_1-42-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 Aβ_1-42-injected TRPA1^+/+ mice, but not in TRPA1^-/- group. Our findings demonstrate that TRPA1 KO animals show substantially reduced morphological damage and memory loss after Aβ_1-42 injection in the SI-NBM. We conclude that TRPA1 receptors may play an important deteriorating role in the Aβ_1-42-induced cholinergic neurotoxicity and the consequent memory loss in the murine brain.

Keywords: Amyloid beta; Cholinergic cell loss; Memory loss; TRPA1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Amyloid beta-Peptides / toxicity*
Animals
Gene Deletion
Mice
Mice, Knockout
Neurotoxicity Syndromes / genetics
Neurotoxicity Syndromes / metabolism*
Neurotoxicity Syndromes / pathology
Peptide Fragments / toxicity*
Prosencephalon / metabolism*
Prosencephalon / pathology
TRPA1 Cation Channel / deficiency*

Substances

Amyloid beta-Peptides
Peptide Fragments
TRPA1 Cation Channel
Trpa1 protein, mouse
amyloid beta-protein (1-42)