Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum
Abstract Background Low-grade, chronic inflammation in the central nervous system characterized by glial reactivity is one of the major hallmarks for aging-related neurodegenerative diseases like Alzheimer’s disease (AD). The basal forebrain cholinergic neurons (BFCN) provide the primary source of c...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-10-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02897-5 |
| _version_ | 1827709257081946112 |
|---|---|
| author | Rashmi Gamage Ilaria Rossetti Garry Niedermayer Gerald Münch Yossi Buskila Erika Gyengesi |
| author_facet | Rashmi Gamage Ilaria Rossetti Garry Niedermayer Gerald Münch Yossi Buskila Erika Gyengesi |
| author_sort | Rashmi Gamage |
| collection | DOAJ |
| description | Abstract Background Low-grade, chronic inflammation in the central nervous system characterized by glial reactivity is one of the major hallmarks for aging-related neurodegenerative diseases like Alzheimer’s disease (AD). The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex and may be differentially vulnerable in various neurodegenerative diseases. However, the impact of chronic neuroinflammation on the cholinergic function is still unclear. Methods To gain further insight into age-related cholinergic decline, we investigated the cumulative effects of aging and chronic neuroinflammation on the structure and function of the septal cholinergic neurons in transgenic mice expressing interleukin-6 under the GFAP promoter (GFAP-IL6), which maintains a constant level of gliosis. Immunohistochemistry combined with unbiased stereology, single cell 3D morphology analysis and in vitro whole cell patch-clamp measurements were used to validate the structural and functional changes of BFCN and their microglial environment in the medial septum. Results Stereological estimation of MS microglia number displayed significant increase across all three age groups, while a significant decrease in cholinergic cell number in the adult and aged groups in GFAP-IL6 mice compared to control. Moreover, we observed age-dependent alterations in the electrophysiological properties of cholinergic neurons and an increased excitability profile in the adult GFAP-IL6 group due to chronic neuroinflammation. These results complimented the significant decrease in hippocampal pyramidal spine density seen with aging and neuroinflammation. Conclusions We provide evidence of the significant impact of both aging and chronic glial activation on the cholinergic and microglial numbers and morphology in the MS, and alterations in the passive and active electrophysiological membrane properties of septal cholinergic neurons, resulting in cholinergic dysfunction, as seen in AD. Our results indicate that aging combined with gliosis is sufficient to cause cholinergic disruptions in the brain, as seen in dementias. |
| first_indexed | 2024-03-10T17:19:24Z |
| format | Article |
| id | doaj.art-8d766713fce74ec48c1cecda614ba762 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-10T17:19:24Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-8d766713fce74ec48c1cecda614ba7622023-11-20T10:24:20ZengBMCJournal of Neuroinflammation1742-20942023-10-0120112410.1186/s12974-023-02897-5Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septumRashmi Gamage0Ilaria Rossetti1Garry Niedermayer2Gerald Münch3Yossi Buskila4Erika Gyengesi5School of Medicine, Western Sydney UniversitySchool of Medicine, Western Sydney UniversitySchool of Science, Western Sydney UniversitySchool of Medicine, Western Sydney UniversitySchool of Medicine, Western Sydney UniversitySchool of Medicine, Western Sydney UniversityAbstract Background Low-grade, chronic inflammation in the central nervous system characterized by glial reactivity is one of the major hallmarks for aging-related neurodegenerative diseases like Alzheimer’s disease (AD). The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex and may be differentially vulnerable in various neurodegenerative diseases. However, the impact of chronic neuroinflammation on the cholinergic function is still unclear. Methods To gain further insight into age-related cholinergic decline, we investigated the cumulative effects of aging and chronic neuroinflammation on the structure and function of the septal cholinergic neurons in transgenic mice expressing interleukin-6 under the GFAP promoter (GFAP-IL6), which maintains a constant level of gliosis. Immunohistochemistry combined with unbiased stereology, single cell 3D morphology analysis and in vitro whole cell patch-clamp measurements were used to validate the structural and functional changes of BFCN and their microglial environment in the medial septum. Results Stereological estimation of MS microglia number displayed significant increase across all three age groups, while a significant decrease in cholinergic cell number in the adult and aged groups in GFAP-IL6 mice compared to control. Moreover, we observed age-dependent alterations in the electrophysiological properties of cholinergic neurons and an increased excitability profile in the adult GFAP-IL6 group due to chronic neuroinflammation. These results complimented the significant decrease in hippocampal pyramidal spine density seen with aging and neuroinflammation. Conclusions We provide evidence of the significant impact of both aging and chronic glial activation on the cholinergic and microglial numbers and morphology in the MS, and alterations in the passive and active electrophysiological membrane properties of septal cholinergic neurons, resulting in cholinergic dysfunction, as seen in AD. Our results indicate that aging combined with gliosis is sufficient to cause cholinergic disruptions in the brain, as seen in dementias.https://doi.org/10.1186/s12974-023-02897-5NeuroinflammationHealthy agingMicrogliaCholinergic systemAnimal-mouseStereology |
| spellingShingle | Rashmi Gamage Ilaria Rossetti Garry Niedermayer Gerald Münch Yossi Buskila Erika Gyengesi Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum Journal of Neuroinflammation Neuroinflammation Healthy aging Microglia Cholinergic system Animal-mouse Stereology |
| title | Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum |
| title_full | Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum |
| title_fullStr | Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum |
| title_full_unstemmed | Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum |
| title_short | Chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum |
| title_sort | chronic neuroinflammation during aging leads to cholinergic neurodegeneration in the mouse medial septum |
| topic | Neuroinflammation Healthy aging Microglia Cholinergic system Animal-mouse Stereology |
| url | https://doi.org/10.1186/s12974-023-02897-5 |
| work_keys_str_mv | AT rashmigamage chronicneuroinflammationduringagingleadstocholinergicneurodegenerationinthemousemedialseptum AT ilariarossetti chronicneuroinflammationduringagingleadstocholinergicneurodegenerationinthemousemedialseptum AT garryniedermayer chronicneuroinflammationduringagingleadstocholinergicneurodegenerationinthemousemedialseptum AT geraldmunch chronicneuroinflammationduringagingleadstocholinergicneurodegenerationinthemousemedialseptum AT yossibuskila chronicneuroinflammationduringagingleadstocholinergicneurodegenerationinthemousemedialseptum AT erikagyengesi chronicneuroinflammationduringagingleadstocholinergicneurodegenerationinthemousemedialseptum |