Cargando…

Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease

Alzheimer disease (AD) is a widespread neurodegenerative disease characterized by the accumulation of oligomeric toxic forms of β-amyloid (Aβ1-42) and dysfunction of the cholinergic system in the different brain regions. However, the exact mechanisms of AD pathogenesis and the role of the nicotinic...

Descripción completa

Detalles Bibliográficos
Autores principales: Bychkov, Maxim L., Isaev, Aizek B., Andreev-Andrievskiy, Alexander A., Petrov, Konstantin, Paramonov, Alexander S., Kirpichnikov, Mikhail P., Lyukmanova, Ekaterina N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10573428/
https://www.ncbi.nlm.nih.gov/pubmed/37834299
http://dx.doi.org/10.3390/ijms241914852
_version_ 1785120461389037568
author Bychkov, Maxim L.
Isaev, Aizek B.
Andreev-Andrievskiy, Alexander A.
Petrov, Konstantin
Paramonov, Alexander S.
Kirpichnikov, Mikhail P.
Lyukmanova, Ekaterina N.
author_facet Bychkov, Maxim L.
Isaev, Aizek B.
Andreev-Andrievskiy, Alexander A.
Petrov, Konstantin
Paramonov, Alexander S.
Kirpichnikov, Mikhail P.
Lyukmanova, Ekaterina N.
author_sort Bychkov, Maxim L.
collection PubMed
description Alzheimer disease (AD) is a widespread neurodegenerative disease characterized by the accumulation of oligomeric toxic forms of β-amyloid (Aβ1-42) and dysfunction of the cholinergic system in the different brain regions. However, the exact mechanisms of AD pathogenesis and the role of the nicotinic acetylcholine receptors (nAChRs) in the disease progression remain unclear. Here, we revealed a decreased expression of a number of the Ly6/uPAR proteins targeting nAChRs in the cerebellum of 2xTg-AD mice (model of early AD) in comparison with non-transgenic mice both at mRNA and protein levels. We showed that co-localization of one of them, – neuromodulator Lynx1, with α7-nAChR was diminished in the vicinity of cerebellar astrocytes of 2xTg-AD mice, while Aβ1-42 co-localization with this receptor present was increased. Moreover, the expression of anti-inflammatory transcription factor KLF4 regulating transcription of the Ly6/uPAR genes was decreased in the cerebellum of 2xTg-AD mice, while expression of inflammatory cytokine TNF-α was increased. Based on these data together with observed astrocyte degeneration in the cerebellum of 2xTg-AD mice, we suggest the mechanism by which expression of the Ly6/uPAR proteins upon Aβ pathology results in dysregulation of the cholinergic system and particularly of α7-nAChR function in the cerebellum. This leads to enhanced neuroinflammation and cerebellar astrocyte degeneration.
format Online
Article
Text
id pubmed-10573428
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-105734282023-10-14 Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease Bychkov, Maxim L. Isaev, Aizek B. Andreev-Andrievskiy, Alexander A. Petrov, Konstantin Paramonov, Alexander S. Kirpichnikov, Mikhail P. Lyukmanova, Ekaterina N. Int J Mol Sci Article Alzheimer disease (AD) is a widespread neurodegenerative disease characterized by the accumulation of oligomeric toxic forms of β-amyloid (Aβ1-42) and dysfunction of the cholinergic system in the different brain regions. However, the exact mechanisms of AD pathogenesis and the role of the nicotinic acetylcholine receptors (nAChRs) in the disease progression remain unclear. Here, we revealed a decreased expression of a number of the Ly6/uPAR proteins targeting nAChRs in the cerebellum of 2xTg-AD mice (model of early AD) in comparison with non-transgenic mice both at mRNA and protein levels. We showed that co-localization of one of them, – neuromodulator Lynx1, with α7-nAChR was diminished in the vicinity of cerebellar astrocytes of 2xTg-AD mice, while Aβ1-42 co-localization with this receptor present was increased. Moreover, the expression of anti-inflammatory transcription factor KLF4 regulating transcription of the Ly6/uPAR genes was decreased in the cerebellum of 2xTg-AD mice, while expression of inflammatory cytokine TNF-α was increased. Based on these data together with observed astrocyte degeneration in the cerebellum of 2xTg-AD mice, we suggest the mechanism by which expression of the Ly6/uPAR proteins upon Aβ pathology results in dysregulation of the cholinergic system and particularly of α7-nAChR function in the cerebellum. This leads to enhanced neuroinflammation and cerebellar astrocyte degeneration. MDPI 2023-10-03 /pmc/articles/PMC10573428/ /pubmed/37834299 http://dx.doi.org/10.3390/ijms241914852 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bychkov, Maxim L.
Isaev, Aizek B.
Andreev-Andrievskiy, Alexander A.
Petrov, Konstantin
Paramonov, Alexander S.
Kirpichnikov, Mikhail P.
Lyukmanova, Ekaterina N.
Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease
title Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease
title_full Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease
title_fullStr Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease
title_full_unstemmed Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease
title_short Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease
title_sort aβ1-42 accumulation accompanies changed expression of ly6/upar proteins, dysregulation of the cholinergic system, and degeneration of astrocytes in the cerebellum of mouse model of early alzheimer disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10573428/
https://www.ncbi.nlm.nih.gov/pubmed/37834299
http://dx.doi.org/10.3390/ijms241914852
work_keys_str_mv AT bychkovmaximl ab142accumulationaccompanieschangedexpressionofly6uparproteinsdysregulationofthecholinergicsystemanddegenerationofastrocytesinthecerebellumofmousemodelofearlyalzheimerdisease
AT isaevaizekb ab142accumulationaccompanieschangedexpressionofly6uparproteinsdysregulationofthecholinergicsystemanddegenerationofastrocytesinthecerebellumofmousemodelofearlyalzheimerdisease
AT andreevandrievskiyalexandera ab142accumulationaccompanieschangedexpressionofly6uparproteinsdysregulationofthecholinergicsystemanddegenerationofastrocytesinthecerebellumofmousemodelofearlyalzheimerdisease
AT petrovkonstantin ab142accumulationaccompanieschangedexpressionofly6uparproteinsdysregulationofthecholinergicsystemanddegenerationofastrocytesinthecerebellumofmousemodelofearlyalzheimerdisease
AT paramonovalexanders ab142accumulationaccompanieschangedexpressionofly6uparproteinsdysregulationofthecholinergicsystemanddegenerationofastrocytesinthecerebellumofmousemodelofearlyalzheimerdisease
AT kirpichnikovmikhailp ab142accumulationaccompanieschangedexpressionofly6uparproteinsdysregulationofthecholinergicsystemanddegenerationofastrocytesinthecerebellumofmousemodelofearlyalzheimerdisease
AT lyukmanovaekaterinan ab142accumulationaccompanieschangedexpressionofly6uparproteinsdysregulationofthecholinergicsystemanddegenerationofastrocytesinthecerebellumofmousemodelofearlyalzheimerdisease