Éverton Carlos Brezolin, Vitor Gayger-Dias, Vanessa-Fernanda Da Silva, Anderson Cigerce, Bruna Schultz, Thomas Michel Sobottka, Patrícia Nardin, Adriano Martimbianco de Assis, Marina Concli Leite, André Quincozes-Santos, Larissa Daniele Bobermin, Carlos-Alberto Gonçalves
{"title":"星形胶质细胞功能障碍改变链脲佐菌素诱导的散发性阿尔茨海默病模型中gaba能通讯和氨代谢。","authors":"Éverton Carlos Brezolin, Vitor Gayger-Dias, Vanessa-Fernanda Da Silva, Anderson Cigerce, Bruna Schultz, Thomas Michel Sobottka, Patrícia Nardin, Adriano Martimbianco de Assis, Marina Concli Leite, André Quincozes-Santos, Larissa Daniele Bobermin, Carlos-Alberto Gonçalves","doi":"10.1177/25424823241289036","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>In the sporadic model of Alzheimer's disease (AD), induced by intracerebroventricular streptozotocin (STZ) administration, cognitive impairment is accompanied by specific astrocytic changes in the hippocampus prior to amyloid deposition.</p><p><strong>Objective: </strong>Hypothesizing that the synthesis of GABA, via MAO-B, contributes to ammonia elevation, thereby compromising antioxidant defense and ATP synthesis, and possibly contributing to cognitive damage, we determined the hippocampal levels of glutamine synthetase (GS), monoamine oxidase B (MAO-B) and other enzymes related to GABA metabolism.</p><p><strong>Methods: </strong>Immunoblotting and RT-PCR assays were carried out in hippocampal samples of Wistar rats, at 4 and 16 weeks post-STZ, in the sporadic STZ-induced AD model, corresponding to the pre-amyloid and amyloid phases, respectively.</p><p><strong>Results: </strong>We observed a reduction in GS activity and increased MAO-B content, both in 4 weeks and in 16 weeks, reinforcing the idea that astroglial dysfunction precedes the amyloid phase. These alterations were accompanied by an increase in the content of ornithine decarboxylase 1 (ODC1), which catalyzes the synthesis of putrescine (substrate for GABA synthesis, via MAO-B), and a reduction in the gene expression of arginine-glycine amidinotransferase (AGAT), an enzyme involved in the synthesis of creatine, and in the generation of GABA agonists. These changes were only seen in the amyloid phase of the AD model.</p><p><strong>Conclusions: </strong>Our findings contribute to explain the greater damage that occurs in energy metabolism at this stage, in addition to the greater GABAergic loss. The changes reinforce the importance of the STZ model and further our understanding of the changes in both AD phases.</p>","PeriodicalId":73594,"journal":{"name":"Journal of Alzheimer's disease reports","volume":"8 1","pages":"1381-1393"},"PeriodicalIF":2.8000,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863748/pdf/","citationCount":"0","resultStr":"{\"title\":\"Astrocyte dysfunction alters GABAergic communication and ammonia metabolism in the streptozotocin-induced sporadic Alzheimer's disease model.\",\"authors\":\"Éverton Carlos Brezolin, Vitor Gayger-Dias, Vanessa-Fernanda Da Silva, Anderson Cigerce, Bruna Schultz, Thomas Michel Sobottka, Patrícia Nardin, Adriano Martimbianco de Assis, Marina Concli Leite, André Quincozes-Santos, Larissa Daniele Bobermin, Carlos-Alberto Gonçalves\",\"doi\":\"10.1177/25424823241289036\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>In the sporadic model of Alzheimer's disease (AD), induced by intracerebroventricular streptozotocin (STZ) administration, cognitive impairment is accompanied by specific astrocytic changes in the hippocampus prior to amyloid deposition.</p><p><strong>Objective: </strong>Hypothesizing that the synthesis of GABA, via MAO-B, contributes to ammonia elevation, thereby compromising antioxidant defense and ATP synthesis, and possibly contributing to cognitive damage, we determined the hippocampal levels of glutamine synthetase (GS), monoamine oxidase B (MAO-B) and other enzymes related to GABA metabolism.</p><p><strong>Methods: </strong>Immunoblotting and RT-PCR assays were carried out in hippocampal samples of Wistar rats, at 4 and 16 weeks post-STZ, in the sporadic STZ-induced AD model, corresponding to the pre-amyloid and amyloid phases, respectively.</p><p><strong>Results: </strong>We observed a reduction in GS activity and increased MAO-B content, both in 4 weeks and in 16 weeks, reinforcing the idea that astroglial dysfunction precedes the amyloid phase. These alterations were accompanied by an increase in the content of ornithine decarboxylase 1 (ODC1), which catalyzes the synthesis of putrescine (substrate for GABA synthesis, via MAO-B), and a reduction in the gene expression of arginine-glycine amidinotransferase (AGAT), an enzyme involved in the synthesis of creatine, and in the generation of GABA agonists. These changes were only seen in the amyloid phase of the AD model.</p><p><strong>Conclusions: </strong>Our findings contribute to explain the greater damage that occurs in energy metabolism at this stage, in addition to the greater GABAergic loss. The changes reinforce the importance of the STZ model and further our understanding of the changes in both AD phases.</p>\",\"PeriodicalId\":73594,\"journal\":{\"name\":\"Journal of Alzheimer's disease reports\",\"volume\":\"8 1\",\"pages\":\"1381-1393\"},\"PeriodicalIF\":2.8000,\"publicationDate\":\"2024-10-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11863748/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Alzheimer's disease reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1177/25424823241289036\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Alzheimer's disease reports","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1177/25424823241289036","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Astrocyte dysfunction alters GABAergic communication and ammonia metabolism in the streptozotocin-induced sporadic Alzheimer's disease model.
Background: In the sporadic model of Alzheimer's disease (AD), induced by intracerebroventricular streptozotocin (STZ) administration, cognitive impairment is accompanied by specific astrocytic changes in the hippocampus prior to amyloid deposition.
Objective: Hypothesizing that the synthesis of GABA, via MAO-B, contributes to ammonia elevation, thereby compromising antioxidant defense and ATP synthesis, and possibly contributing to cognitive damage, we determined the hippocampal levels of glutamine synthetase (GS), monoamine oxidase B (MAO-B) and other enzymes related to GABA metabolism.
Methods: Immunoblotting and RT-PCR assays were carried out in hippocampal samples of Wistar rats, at 4 and 16 weeks post-STZ, in the sporadic STZ-induced AD model, corresponding to the pre-amyloid and amyloid phases, respectively.
Results: We observed a reduction in GS activity and increased MAO-B content, both in 4 weeks and in 16 weeks, reinforcing the idea that astroglial dysfunction precedes the amyloid phase. These alterations were accompanied by an increase in the content of ornithine decarboxylase 1 (ODC1), which catalyzes the synthesis of putrescine (substrate for GABA synthesis, via MAO-B), and a reduction in the gene expression of arginine-glycine amidinotransferase (AGAT), an enzyme involved in the synthesis of creatine, and in the generation of GABA agonists. These changes were only seen in the amyloid phase of the AD model.
Conclusions: Our findings contribute to explain the greater damage that occurs in energy metabolism at this stage, in addition to the greater GABAergic loss. The changes reinforce the importance of the STZ model and further our understanding of the changes in both AD phases.