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Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity

Alzheimer’s disease (AD), one of the most widespread neurodegenerative disorder, is a fatal global burden for the elder population. Although many efforts have been made, the search of a curative therapy is still ongoing. Individuating phenotypic traits that might help in investigating treatment resp...

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Autores principales: Morgese, Maria Grazia, Bove, Maria, Di Cesare Mannelli, Lorenzo, Schiavone, Stefania, Colia, Anna Laura, Dimonte, Stefania, Mhillaj, Emanuela, Sikora, Vladyslav, Tucci, Paolo, Ghelardini, Carla, Trabace, Luigia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8763383/
https://www.ncbi.nlm.nih.gov/pubmed/35046821
http://dx.doi.org/10.3389/fphar.2021.799561
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author Morgese, Maria Grazia
Bove, Maria
Di Cesare Mannelli, Lorenzo
Schiavone, Stefania
Colia, Anna Laura
Dimonte, Stefania
Mhillaj, Emanuela
Sikora, Vladyslav
Tucci, Paolo
Ghelardini, Carla
Trabace, Luigia
author_facet Morgese, Maria Grazia
Bove, Maria
Di Cesare Mannelli, Lorenzo
Schiavone, Stefania
Colia, Anna Laura
Dimonte, Stefania
Mhillaj, Emanuela
Sikora, Vladyslav
Tucci, Paolo
Ghelardini, Carla
Trabace, Luigia
author_sort Morgese, Maria Grazia
collection PubMed
description Alzheimer’s disease (AD), one of the most widespread neurodegenerative disorder, is a fatal global burden for the elder population. Although many efforts have been made, the search of a curative therapy is still ongoing. Individuating phenotypic traits that might help in investigating treatment response is of growing interest in AD research. AD is a complex pathology characterized by many comorbidities, such as depression and increased susceptibility to pain perception, leading to postulate that these conditions may rely on common biological substrates yet to be determined. In order to investigate those biological determinants to be associable with phenotypic traits, we used the rat model of amyloid beta-induced toxicity. This established model of early phase of AD is obtained by the intracerebroventricular injection of soluble amyloid beta1-42 (Aβ) peptide 7 days before performing experiments. In this model, we have previously reported increased immobility in the forced swimming test, reduced cortical serotonin levels and subtle alterations in the cognitive domain a depressive-like phenotype associated with subtle alteration in memory processes. In light of evaluating pain perception in this animal model, we performed two different behavioral tests commonly used, such as the paw pressure test and the cold plate test, to analyze mechanical hyperalgesia and thermal allodynia, respectively. Behavioural outcomes confirmed the memory impairment in the social recognition test and, compared to sham, Aβ-injected rats showed an increased selective susceptibility to mechanical but not to thermal stimulus. Behavioural data were then corroborated by neurochemical and biochemical biomarker analyses either at central or peripheral level. Data showed that the peptide injection evoked a significant increase in hypothalamic glutamate, kynurenine and dopamine content, while serotonin levels were reduced. Plasma Cystatin-C, a cysteine protease, was increased while serotonin and melatonin levels were decreased in Aβ-injected rats. Urinary levels paralleled plasma quantifications, indicating that Aβ-induced deficits in pain perception, mood and cognitive domain may also depend on these biomarkers. In conclusion, in the present study, we demonstrated that this animal model can mimic several comorbid conditions typical of the early phase of AD. Therefore, in the perspective of generating novel therapeutic strategies relevant to precision medicine in AD, this animal model and the biomarkers evaluated herein may represent an advantageous approach.
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spelling pubmed-87633832022-01-18 Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity Morgese, Maria Grazia Bove, Maria Di Cesare Mannelli, Lorenzo Schiavone, Stefania Colia, Anna Laura Dimonte, Stefania Mhillaj, Emanuela Sikora, Vladyslav Tucci, Paolo Ghelardini, Carla Trabace, Luigia Front Pharmacol Pharmacology Alzheimer’s disease (AD), one of the most widespread neurodegenerative disorder, is a fatal global burden for the elder population. Although many efforts have been made, the search of a curative therapy is still ongoing. Individuating phenotypic traits that might help in investigating treatment response is of growing interest in AD research. AD is a complex pathology characterized by many comorbidities, such as depression and increased susceptibility to pain perception, leading to postulate that these conditions may rely on common biological substrates yet to be determined. In order to investigate those biological determinants to be associable with phenotypic traits, we used the rat model of amyloid beta-induced toxicity. This established model of early phase of AD is obtained by the intracerebroventricular injection of soluble amyloid beta1-42 (Aβ) peptide 7 days before performing experiments. In this model, we have previously reported increased immobility in the forced swimming test, reduced cortical serotonin levels and subtle alterations in the cognitive domain a depressive-like phenotype associated with subtle alteration in memory processes. In light of evaluating pain perception in this animal model, we performed two different behavioral tests commonly used, such as the paw pressure test and the cold plate test, to analyze mechanical hyperalgesia and thermal allodynia, respectively. Behavioural outcomes confirmed the memory impairment in the social recognition test and, compared to sham, Aβ-injected rats showed an increased selective susceptibility to mechanical but not to thermal stimulus. Behavioural data were then corroborated by neurochemical and biochemical biomarker analyses either at central or peripheral level. Data showed that the peptide injection evoked a significant increase in hypothalamic glutamate, kynurenine and dopamine content, while serotonin levels were reduced. Plasma Cystatin-C, a cysteine protease, was increased while serotonin and melatonin levels were decreased in Aβ-injected rats. Urinary levels paralleled plasma quantifications, indicating that Aβ-induced deficits in pain perception, mood and cognitive domain may also depend on these biomarkers. In conclusion, in the present study, we demonstrated that this animal model can mimic several comorbid conditions typical of the early phase of AD. Therefore, in the perspective of generating novel therapeutic strategies relevant to precision medicine in AD, this animal model and the biomarkers evaluated herein may represent an advantageous approach. Frontiers Media S.A. 2022-01-03 /pmc/articles/PMC8763383/ /pubmed/35046821 http://dx.doi.org/10.3389/fphar.2021.799561 Text en Copyright © 2022 Morgese, Bove, Di Cesare Mannelli, Schiavone, Colia, Dimonte, Mhillaj, Sikora, Tucci, Ghelardini and Trabace. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Morgese, Maria Grazia
Bove, Maria
Di Cesare Mannelli, Lorenzo
Schiavone, Stefania
Colia, Anna Laura
Dimonte, Stefania
Mhillaj, Emanuela
Sikora, Vladyslav
Tucci, Paolo
Ghelardini, Carla
Trabace, Luigia
Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity
title Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity
title_full Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity
title_fullStr Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity
title_full_unstemmed Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity
title_short Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity
title_sort precision medicine in alzheimer’s disease: investigating comorbid common biological substrates in the rat model of amyloid beta-induced toxicity
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8763383/
https://www.ncbi.nlm.nih.gov/pubmed/35046821
http://dx.doi.org/10.3389/fphar.2021.799561
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