Lin-Heng Zhang, Hong‐Yi Yang, Jing Wu, Yun Wu, Luwan Wang, Haiyang Tong, Jin Zhang, Wenchao Wang, Rongyao Huang, Jiang-Lei Xu, Jing Su, Xun-Ran Luo, Yong Yin, Shi-Hao Wu, Xinyong Hu
Intracerebroventricular (ICV) administration through cannulas is a direct way to deliver large molecules and substances that are blocked by the blood-brain barrier into the central nervous system (CNS). It is widely used in brain studies on monkeys. However, this method is invasive, as it requires guide cannulas to be implanted into the brain. Whether the long-term implantation of the cannula and the administration of molecule-delivering vehicles, usually saline, can affect the brain by inducing chronic CNS inflammation or even worse brain atrophy, remains an issue to be solved. To answer this question, we investigated inflammatory markers and brain structures on three vehicle-control monkeys who received cannula implantation and one-year ICV saline administration in another study. During the experiment, the monkeys’ cerebrospinal fluid (CSF) samples were collected periodically, and the level of three classic inflammatory markers (IL-1β, IL-6, and TNF-α) were measured by electrochemiluminescence immunoassay. The monkeys’ brain structures were imaged in vivo periodically by 9.4 Tesla magnetic resonance imaging, which can provide the best-resolution magnetic resonance images of living monkeys, and the volume of the hippocampus was measured to evaluate the brain atrophy. The data reveal that, during the administrating period, the long-term levels of the inflammatory markers in the CSF and the volumes of the hippocampus did not change significantly compared with the baseline. These results suggest that the long-term ICV administration of saline through cannulas did not induce chronic neuroinflammation or brain atrophy in these rhesus monkeys, suggesting chronic ICV administration via implanted cannulas is a reliable method in monkey brain research.
{"title":"Chronic intracerebroventricular administration is a reliable method in brain studies on monkeys","authors":"Lin-Heng Zhang, Hong‐Yi Yang, Jing Wu, Yun Wu, Luwan Wang, Haiyang Tong, Jin Zhang, Wenchao Wang, Rongyao Huang, Jiang-Lei Xu, Jing Su, Xun-Ran Luo, Yong Yin, Shi-Hao Wu, Xinyong Hu","doi":"10.20517/and.2022.02","DOIUrl":"https://doi.org/10.20517/and.2022.02","url":null,"abstract":"Intracerebroventricular (ICV) administration through cannulas is a direct way to deliver large molecules and substances that are blocked by the blood-brain barrier into the central nervous system (CNS). It is widely used in brain studies on monkeys. However, this method is invasive, as it requires guide cannulas to be implanted into the brain. Whether the long-term implantation of the cannula and the administration of molecule-delivering vehicles, usually saline, can affect the brain by inducing chronic CNS inflammation or even worse brain atrophy, remains an issue to be solved. To answer this question, we investigated inflammatory markers and brain structures on three vehicle-control monkeys who received cannula implantation and one-year ICV saline administration in another study. During the experiment, the monkeys’ cerebrospinal fluid (CSF) samples were collected periodically, and the level of three classic inflammatory markers (IL-1β, IL-6, and TNF-α) were measured by electrochemiluminescence immunoassay. The monkeys’ brain structures were imaged in vivo periodically by 9.4 Tesla magnetic resonance imaging, which can provide the best-resolution magnetic resonance images of living monkeys, and the volume of the hippocampus was measured to evaluate the brain atrophy. The data reveal that, during the administrating period, the long-term levels of the inflammatory markers in the CSF and the volumes of the hippocampus did not change significantly compared with the baseline. These results suggest that the long-term ICV administration of saline through cannulas did not induce chronic neuroinflammation or brain atrophy in these rhesus monkeys, suggesting chronic ICV administration via implanted cannulas is a reliable method in monkey brain research.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80462148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
U. Habiba, J. Morley, M. Krockenberger, B. Summers, M. Tayebi
Aims: Cerebral amyloid burdens may be found in otherwise cognitively intact adults, often not showing worsening deficits with passing years. Alzheimer’s transgenic rodents have been widely used to investigate this phenomenon, but a spontaneous disorder in other animals, such as dogs that cohabit with humans and thus may have some shared environmental risks, may contribute and offer opportunities not possible in the smaller laboratory animals. In animals, the spontaneous disorder most comparable to Alzheimer’s disease (AD) affects mature to aged dogs and is designated canine cognitive dysfunction. Motivated by AD, many studies have revealed that amyloid progressively accumulates in the canine central nervous system, including the retina. Here, we investigated whether deposits of amyloid and/or tau can be found in the canine retina of neurologically normal animals from the first year of life to the elderly. Suppose canine ocular amyloid and tau are present from early life. In that case, that raises the question of whether similar patterns of accumulation occur in man, whether as part of aging, AD, or other. Methods: This study used eye tissues from 30 dogs with a variety of ophthalmic or other orbital disorders, of which 7/30 were 1-2 years old. Tissues were subdivided into dogs of three different age groups: young (1-5 years old), middle (6-10 years old), and old (≥ 11 years old). Results: Following immunostaining of tissue sections with nanobodies against retinal Aβ1-40 and Aβ1-42 oligomers, and antibodies against Aβ plaques (Aβp) and hyperphosphorylated Tau (p-Tau), our investigations revealed that accumulation of Aβ1-40 and Aβ1-42 oligomers were widespread in the retina in all age groups. In contrast, Aβp were detected in the middle and old age groups but not in the young age group. Furthermore, p-Tau staining was observed in four old dogs only, while other dogs were p-Tau free. Interestingly, both Aβo and Aβp co-localized in the middle and old age groups of dogs. Moreover, diffuse granular p-Tau co-localized with intracellular Aβo in the old age group. Finally, we also observed co-localization of Aβo and Aβp in the retinal vasculature which might be similar to cerebral amyloid angiopathy associated with AD. Conclusion: As far as we know, the presence of amyloid and tau in the canine retina is hitherto unreported. If similar, early-in-life subclinical retinal deposits occur in a human cohort perhaps identified by AD genetic risk factors, following this group may offer the prospect of preclinical therapeutic intervention in imminent dementia, a strategy recognized as likely necessary to impact this burgeoning disorder.
{"title":"A sequential deposition of amyloid beta oligomers, plaques and phosphorylated tau occurs throughout life in the canine retina","authors":"U. Habiba, J. Morley, M. Krockenberger, B. Summers, M. Tayebi","doi":"10.20517/and.2022.06","DOIUrl":"https://doi.org/10.20517/and.2022.06","url":null,"abstract":"Aims: Cerebral amyloid burdens may be found in otherwise cognitively intact adults, often not showing worsening deficits with passing years. Alzheimer’s transgenic rodents have been widely used to investigate this phenomenon, but a spontaneous disorder in other animals, such as dogs that cohabit with humans and thus may have some shared environmental risks, may contribute and offer opportunities not possible in the smaller laboratory animals. In animals, the spontaneous disorder most comparable to Alzheimer’s disease (AD) affects mature to aged dogs and is designated canine cognitive dysfunction. Motivated by AD, many studies have revealed that amyloid progressively accumulates in the canine central nervous system, including the retina. Here, we investigated whether deposits of amyloid and/or tau can be found in the canine retina of neurologically normal animals from the first year of life to the elderly. Suppose canine ocular amyloid and tau are present from early life. In that case, that raises the question of whether similar patterns of accumulation occur in man, whether as part of aging, AD, or other. Methods: This study used eye tissues from 30 dogs with a variety of ophthalmic or other orbital disorders, of which 7/30 were 1-2 years old. Tissues were subdivided into dogs of three different age groups: young (1-5 years old), middle (6-10 years old), and old (≥ 11 years old). Results: Following immunostaining of tissue sections with nanobodies against retinal Aβ1-40 and Aβ1-42 oligomers, and antibodies against Aβ plaques (Aβp) and hyperphosphorylated Tau (p-Tau), our investigations revealed that accumulation of Aβ1-40 and Aβ1-42 oligomers were widespread in the retina in all age groups. In contrast, Aβp were detected in the middle and old age groups but not in the young age group. Furthermore, p-Tau staining was observed in four old dogs only, while other dogs were p-Tau free. Interestingly, both Aβo and Aβp co-localized in the middle and old age groups of dogs. Moreover, diffuse granular p-Tau co-localized with intracellular Aβo in the old age group. Finally, we also observed co-localization of Aβo and Aβp in the retinal vasculature which might be similar to cerebral amyloid angiopathy associated with AD. Conclusion: As far as we know, the presence of amyloid and tau in the canine retina is hitherto unreported. If similar, early-in-life subclinical retinal deposits occur in a human cohort perhaps identified by AD genetic risk factors, following this group may offer the prospect of preclinical therapeutic intervention in imminent dementia, a strategy recognized as likely necessary to impact this burgeoning disorder.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73910685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The current novel therapeutic approach suggests that multi-targeted compounds, with diverse biological activities but a single set of bioavailability and pharmacokinetics, will be significantly more advantageous in the treatment of the complex pathology of Parkinson’s diseases (PD) than traditional therapies. This review introduces a novel cholinesterase (ChE)-monoamine oxidase (MAO) inhibitor, namely MT-031, which was designed by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor and neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the methylamino position of the ChE inhibitor anti-AD drug, rivastigmine. MT-031 possesses neuroprotective, cognition enhancing, anti-depressant, and anti-inflammatory properties both in vitro and in vivo. Altogether, these findings suggest that MT-031 may be a potential treatment for combating PD and associated dementia and depression.
{"title":"A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson’s disease","authors":"Wei Liu, Yuqiang Wang, M. Youdim","doi":"10.20517/and.2021.09","DOIUrl":"https://doi.org/10.20517/and.2021.09","url":null,"abstract":"The current novel therapeutic approach suggests that multi-targeted compounds, with diverse biological activities but a single set of bioavailability and pharmacokinetics, will be significantly more advantageous in the treatment of the complex pathology of Parkinson’s diseases (PD) than traditional therapies. This review introduces a novel cholinesterase (ChE)-monoamine oxidase (MAO) inhibitor, namely MT-031, which was designed by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor and neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the methylamino position of the ChE inhibitor anti-AD drug, rivastigmine. MT-031 possesses neuroprotective, cognition enhancing, anti-depressant, and anti-inflammatory properties both in vitro and in vivo. Altogether, these findings suggest that MT-031 may be a potential treatment for combating PD and associated dementia and depression.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90782515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Exemplified by the disproportionate cases of Alzheimer’s disease among women, many diseases show considerable sexual disparity in the aging process. Given that such a sex bias varies significantly in different neurological conditions, considering sex differences is necessary for the diagnosis as well as the treatment of neurological disorders. However, currently, relatively few studies have specifically focused on sex differences in brain aging or the general aging process, which has prevented the development of precision medicine for these sex-different diseases. Here, we summarize age-related disparities relating to cognitive function and dysfunction for males and females from human cross-sectional and longitudinal studies. By discussing potential anatomical and physiological bases underlying such differences, we highlight the importance of sex for aging studies in this review, which may hopefully shed light on understanding the precise causes of different brain diseases.
{"title":"Recent developments in understanding brain aging: sex differences, mechanisms, and implications in diseases","authors":"Jing Yang, Jing Qu, Huan Ma","doi":"10.20517/and.2022.03","DOIUrl":"https://doi.org/10.20517/and.2022.03","url":null,"abstract":"Exemplified by the disproportionate cases of Alzheimer’s disease among women, many diseases show considerable sexual disparity in the aging process. Given that such a sex bias varies significantly in different neurological conditions, considering sex differences is necessary for the diagnosis as well as the treatment of neurological disorders. However, currently, relatively few studies have specifically focused on sex differences in brain aging or the general aging process, which has prevented the development of precision medicine for these sex-different diseases. Here, we summarize age-related disparities relating to cognitive function and dysfunction for males and females from human cross-sectional and longitudinal studies. By discussing potential anatomical and physiological bases underlying such differences, we highlight the importance of sex for aging studies in this review, which may hopefully shed light on understanding the precise causes of different brain diseases.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"141 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77454034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Animal models have great importance in the research of human neurodegenerative diseases due to their value in symptom mimicking, mechanism investigation, and preclinical tests. Although non-human primate and large animal models have good performance in disease modeling due to their high maintenance cost and critical ethical standards, rodent models are commonly used. Rodent models have been successfully applied in modeling many neurological diseases; however, their genetic background, neuroanatomical features, and nervous system development are different from those of humans. Moreover, the short lifespan and small body size of rodent models also limit the monitoring of disease progression and observation of clinical symptoms in studying neuronal disorders that are late-onset or have a long course of progression. In comparison with rodents, rabbits are phylogenetically closer to humans and have closer similarities to humans in brain development, thus are an alternate animal model for human neurological diseases.
{"title":"Genome-edited rabbit, a prospective alternative model for neurological diseases","authors":"Zhongtian Zhang, Yuning Song, L. Lai, Zhanjun Li","doi":"10.20517/and.2022.15","DOIUrl":"https://doi.org/10.20517/and.2022.15","url":null,"abstract":"Animal models have great importance in the research of human neurodegenerative diseases due to their value in symptom mimicking, mechanism investigation, and preclinical tests. Although non-human primate and large animal models have good performance in disease modeling due to their high maintenance cost and critical ethical standards, rodent models are commonly used. Rodent models have been successfully applied in modeling many neurological diseases; however, their genetic background, neuroanatomical features, and nervous system development are different from those of humans. Moreover, the short lifespan and small body size of rodent models also limit the monitoring of disease progression and observation of clinical symptoms in studying neuronal disorders that are late-onset or have a long course of progression. In comparison with rodents, rabbits are phylogenetically closer to humans and have closer similarities to humans in brain development, thus are an alternate animal model for human neurological diseases.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90058775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qingshan Wang, Sheng Song, Lulu Jiang, Jau-Shyong Hong
The role of norepinephrine (NE) in the pathogenesis of Parkinson’s disease (PD) has not been well investigated until recently. The purpose of this perspective article is to review evidence supporting the idea that dysfunction of the locus coeruleus (LC)/NE system in the brain may be fundamentally linked to the pathogenesis of PD. Compelling evidence demonstrates that loss of NE neurons in the LC is sufficient to initiate chronic neuroinflammation, resulting in a progressive and sequential loss of neuronal populations in the brain. This article summarizes the critical role of both microglial and neuronal NADPH oxidase 2 (NOX2), the superoxide and reactive oxygen species generating enzyme, as an important regulator of chronic neuroinflammation. Moreover, NOX2 inhibitors show high efficacy in halting chronic neuroinflammation, oxidative damage, and neurodegeneration in several animal PD models. This line of research offers a promising disease-modifying therapeutic strategy for PD.
{"title":"Interplay among norepinephrine, NOX2, and neuroinflammation: key players in Parkinson’s disease and prime targets for therapies","authors":"Qingshan Wang, Sheng Song, Lulu Jiang, Jau-Shyong Hong","doi":"10.20517/and.2021.06","DOIUrl":"https://doi.org/10.20517/and.2021.06","url":null,"abstract":"The role of norepinephrine (NE) in the pathogenesis of Parkinson’s disease (PD) has not been well investigated until recently. The purpose of this perspective article is to review evidence supporting the idea that dysfunction of the locus coeruleus (LC)/NE system in the brain may be fundamentally linked to the pathogenesis of PD. Compelling evidence demonstrates that loss of NE neurons in the LC is sufficient to initiate chronic neuroinflammation, resulting in a progressive and sequential loss of neuronal populations in the brain. This article summarizes the critical role of both microglial and neuronal NADPH oxidase 2 (NOX2), the superoxide and reactive oxygen species generating enzyme, as an important regulator of chronic neuroinflammation. Moreover, NOX2 inhibitors show high efficacy in halting chronic neuroinflammation, oxidative damage, and neurodegeneration in several animal PD models. This line of research offers a promising disease-modifying therapeutic strategy for PD.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82115168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
article: Mild cognitive impairment vs . mild cognitive dysfunctions: validation with a nomothetic network approach. Abstract Aim: No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral, and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). We aimed to clinically define and biologically validate a subgroup of aMCI subjects who take up an intermediate position between controls and AD patients. age, and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group ( n = 45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD. Conclusion: Petersen’s aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class. statistical significance. Two-step cluster analysis was employed to define clusters of patients based on the cognitome and phenome features. Nearest neighbor analysis was employed to classify subjects based on their feature similarities. All statistical analyses were performed using IBM SPSS windows version 25. phenome latent vectors extracted by PLS scores (3k, Euclidian distance, training sample of 70%, and a holdout sample of 30%), and this analysis showed 45.0% misclassifications in both the training and holdout samples with many aMCI subjects being allocated to the normal control class.
文章:轻度认知障碍vs。轻度认知功能障碍:用本体网络方法验证。目的:载脂蛋白E4 (ApoE4)等位基因与外周生物标志物、高血压和2型糖尿病(T2DM)之间的相互作用是否会影响遗忘性轻度认知障碍(aMCI)和阿尔茨海默病(AD)患者的神经认知、行为和社会功能障碍，目前尚无研究。我们的目的是临床定义和生物学验证一个介于对照组和AD患者之间的aMCI受试者亚组。年龄和教育。使用OBD指数构建三个亚组(正常、中等和高OBD)，中等组(n = 45)在记忆、语言、定向和ADL方面表现为轻度认知功能障碍(MCD)。MCD患者的OBD和BIORISK评分与对照组和AD显著不同。结论:Petersen的aMCI标准不能被验证，应该被更严格的、生物学验证的MCD分类所取代。统计学意义。采用两步聚类分析，根据认知组和表型组特征确定患者聚类。采用最近邻分析法，根据特征相似性对被试进行分类。所有统计分析均使用IBM SPSS windows version 25进行。通过PLS评分(3k，欧氏距离，训练样本为70%，保留样本为30%)提取的表型潜在向量，该分析显示，在训练样本和保留样本中，有45.0%的错误分类，其中许多aMCI受试者被分配到正常对照类。
{"title":"Mild cognitive impairment vs. mild cognitive dysfunctions: validation with a nomothetic network approach","authors":"M. Maes, S. Tangwongchai","doi":"10.20517/and.2021.08","DOIUrl":"https://doi.org/10.20517/and.2021.08","url":null,"abstract":"article: Mild cognitive impairment vs . mild cognitive dysfunctions: validation with a nomothetic network approach. Abstract Aim: No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral, and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). We aimed to clinically define and biologically validate a subgroup of aMCI subjects who take up an intermediate position between controls and AD patients. age, and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group ( n = 45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD. Conclusion: Petersen’s aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class. statistical significance. Two-step cluster analysis was employed to define clusters of patients based on the cognitome and phenome features. Nearest neighbor analysis was employed to classify subjects based on their feature similarities. All statistical analyses were performed using IBM SPSS windows version 25. phenome latent vectors extracted by PLS scores (3k, Euclidian distance, training sample of 70%, and a holdout sample of 30%), and this analysis showed 45.0% misclassifications in both the training and holdout samples with many aMCI subjects being allocated to the normal control class.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"86 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89681597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Wolters, T. Strekalova, J. P. Munter, B. Kramer
Naive BM-derived stem cells (Neuro-Cells) may modify acute and chronic neurodegenerative disorders by modulating macrophage behaviors. Ageing Neur Abstract In acute traumatic or hypoxic brain and spinal cord lesions, as well as in chronic idiopathic neurodegenerative disorders induced by a genetic/environmental/idiopathic protein misfolding with aggregation, emerging evidence indicates that primary necrosis, as induced by the underlying event, initiates a secondary inflammatory process. In this secondary process, responsible for significant neurological deterioration, a microglia type M1/M2 misbalance plays a major role. Indeed, both acute and chronic neurodegenerative disorders share a common pathway: a M1/M2 misbalance-induced hyperinflammatory process with a lack of response to conventional anti-inflammatory interventions. In recent literature, however, both in preclinical and clinical neurodegenerative conditions, these processes were suggested to be sensitive for interventions with stem cells. Intrathecal interventions with a fresh, not-manipulated (naïve) bone marrow-derived stem cell preparation, after positive selection of pro-inflammatory substances (Neuro-Cells), were found to prevent/reduce secondary necrosis-induced pro-inflammatory and pro-apoptotic processes in both immune-compromised and otherwise healthy experimental animal models. Therefore, it seems justified to further encourage clinical trials applying autologous BM-derived naïve stem cells in patients suffering from those debilitating neurodegenerative conditions.
{"title":"Naive BM-derived stem cells (Neuro-Cells) may modify acute and chronic neurodegenerative disorders by modulating macrophage behaviors","authors":"E. Wolters, T. Strekalova, J. P. Munter, B. Kramer","doi":"10.20517/and.2021.04","DOIUrl":"https://doi.org/10.20517/and.2021.04","url":null,"abstract":"Naive BM-derived stem cells (Neuro-Cells) may modify acute and chronic neurodegenerative disorders by modulating macrophage behaviors. Ageing Neur Abstract In acute traumatic or hypoxic brain and spinal cord lesions, as well as in chronic idiopathic neurodegenerative disorders induced by a genetic/environmental/idiopathic protein misfolding with aggregation, emerging evidence indicates that primary necrosis, as induced by the underlying event, initiates a secondary inflammatory process. In this secondary process, responsible for significant neurological deterioration, a microglia type M1/M2 misbalance plays a major role. Indeed, both acute and chronic neurodegenerative disorders share a common pathway: a M1/M2 misbalance-induced hyperinflammatory process with a lack of response to conventional anti-inflammatory interventions. In recent literature, however, both in preclinical and clinical neurodegenerative conditions, these processes were suggested to be sensitive for interventions with stem cells. Intrathecal interventions with a fresh, not-manipulated (naïve) bone marrow-derived stem cell preparation, after positive selection of pro-inflammatory substances (Neuro-Cells), were found to prevent/reduce secondary necrosis-induced pro-inflammatory and pro-apoptotic processes in both immune-compromised and otherwise healthy experimental animal models. Therefore, it seems justified to further encourage clinical trials applying autologous BM-derived naïve stem cells in patients suffering from those debilitating neurodegenerative conditions.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91331425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Karabiyik, Rebecca A. Frake, So Jung Park, Mariana Pavel, D. Rubinsztein
Autophagy is a catabolic mechanism that allows cells to deliver cytoplasmic contents to lysosomes for degradation to maintain energy homeostasis and to protect cells against stress. Autophagy has been directly linked to neurodegeneration and ageing by an extensive body of research. It has become evident that disruption of autophagy contributes significantly to age-related pathologies and to the cognitive and motor declines associated with “healthy” ageing. Autophagic dysfunction causes the accumulation of many of the toxic, aggregate-prone proteins that are responsible for neurodegenerative diseases, including mutant huntingtin, alpha-synuclein, tau, and others. Since upregulation of autophagy has been found to reduce levels of such protein species, the therapeutic potential of autophagy induction as a strategy against age-related diseases and a method for modulating longevity has been widely studied. Here we review the evidence supporting a role for autophagy dysfunction in the progression of the age-associated functional decline in the brain and age-related brain pathologies and discuss the available evidence that upregulation of autophagy may be a valuable therapeutic strategy.
{"title":"Autophagy in ageing and ageing-related neurodegenerative diseases","authors":"C. Karabiyik, Rebecca A. Frake, So Jung Park, Mariana Pavel, D. Rubinsztein","doi":"10.20517/and.2021.05","DOIUrl":"https://doi.org/10.20517/and.2021.05","url":null,"abstract":"Autophagy is a catabolic mechanism that allows cells to deliver cytoplasmic contents to lysosomes for degradation to maintain energy homeostasis and to protect cells against stress. Autophagy has been directly linked to neurodegeneration and ageing by an extensive body of research. It has become evident that disruption of autophagy contributes significantly to age-related pathologies and to the cognitive and motor declines associated with “healthy” ageing. Autophagic dysfunction causes the accumulation of many of the toxic, aggregate-prone proteins that are responsible for neurodegenerative diseases, including mutant huntingtin, alpha-synuclein, tau, and others. Since upregulation of autophagy has been found to reduce levels of such protein species, the therapeutic potential of autophagy induction as a strategy against age-related diseases and a method for modulating longevity has been widely studied. Here we review the evidence supporting a role for autophagy dysfunction in the progression of the age-associated functional decline in the brain and age-related brain pathologies and discuss the available evidence that upregulation of autophagy may be a valuable therapeutic strategy.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84889494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-01-01Epub Date: 2021-07-15DOI: 10.20517/and.2021.07
Kathleen Carmichael, Breanna Sullivan, Elena Lopez, Lixin Sun, Huaibin Cai
Parkinson's disease (PD), the most common degenerative movement disorder, is clinically manifested with various motor and non-motor symptoms. Degeneration of midbrain substantia nigra pas compacta (SNc) dopaminergic neurons (DANs) is generally attributed to the motor syndrome. The underlying neuronal mechanisms of non-motor syndrome are largely unexplored. Besides SNc, midbrain ventral tegmental area (VTA) DANs also produce and release dopamine and modulate movement, reward, motivation, and memory. Degeneration of VTA DANs also occurs in postmortem brains of PD patients, implying an involvement of VTA DANs in PD-associated non-motor symptoms. However, it remains to be established that there is a distinct segregation of different SNc and VTA DAN subtypes in regulating different motor and non-motor functions, and that different DAN subpopulations are differentially affected by normal ageing or PD. Traditionally, the distinction among different DAN subtypes was mainly based on the location of cell bodies and axon terminals. With the recent advance of single cell RNA sequencing technology, DANs can be readily classified based on unique gene expression profiles. A combination of specific anatomic and molecular markers shows great promise to facilitate the identification of DAN subpopulations corresponding to different behavior modules under normal and disease conditions. In this review, we first summarize the recent progress in characterizing genetically, anatomically, and functionally diverse midbrain DAN subtypes. Then, we provide perspectives on how the preclinical research on the connectivity and functionality of DAN subpopulations improves our current understanding of cell-type and circuit specific mechanisms of the disease, which could be critically informative for designing new mechanistic treatments.
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