Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway
Abstract Aberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early pha...
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-022-01396-7 |
| _version_ | 1811227177769762816 |
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| author | Yann Dromard Margarita Arango-Lievano Amelie Borie Maheva Dedin Pierre Fontanaud Joan Torrent Michael J. Garabedian Stephen D. Ginsberg Freddy Jeanneteau |
| author_facet | Yann Dromard Margarita Arango-Lievano Amelie Borie Maheva Dedin Pierre Fontanaud Joan Torrent Michael J. Garabedian Stephen D. Ginsberg Freddy Jeanneteau |
| author_sort | Yann Dromard |
| collection | DOAJ |
| description | Abstract Aberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early phase of AD-like progression in the well-established APP/PS1 mouse model combined with targeted mutations in the BDNF-dependent GR phosphorylation sites (serines 134/267) using molecular, behavioral and neuroimaging approaches. We found that disrupting GR phosphorylation (S134A/S267A) in mice exacerbated the deleterious effects of the APP/PS1 genotype on mortality, neuroplasticity and cognition, without affecting either amyloid-β deposition or vascular pathology. The dynamics, maturation and retention of task-induced new dendritic spines of cortical excitatory neurons required GR phosphorylation at the BDNF-dependent sites that amyloid-β compromised. Parallel studies in postmortem human prefrontal cortex revealed AD subjects had downregulated BDNF signaling and concomitant upregulated cortisol pathway activation, which correlated with cognitive decline. These results provide key evidence that the loss of neurotrophin-mediated GR phosphorylation pathway promotes the detrimental effects of the brain cortisol response that contributes to the onset and/or progression of AD dementia. These findings have important translational implications as they provide a novel approach to treating AD dementia by identifying drugs that increase GR phosphorylation selectively at the neurotrophic sites to improve memory and cognition. |
| first_indexed | 2024-04-12T09:38:07Z |
| format | Article |
| id | doaj.art-bdb580aaa89e4d659e96d398751ab03b |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-04-12T09:38:07Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-bdb580aaa89e4d659e96d398751ab03b2022-12-22T03:38:10ZengBMCActa Neuropathologica Communications2051-59602022-06-0110111710.1186/s40478-022-01396-7Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathwayYann Dromard0Margarita Arango-Lievano1Amelie Borie2Maheva Dedin3Pierre Fontanaud4Joan Torrent5Michael J. Garabedian6Stephen D. Ginsberg7Freddy Jeanneteau8Institut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRSInstitut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRSInstitut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRSInstitut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRSInstitut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRSInstitut de Neuroscience de Montpellier, INSERMDepartment of Microbiology, New York University Grossman School of MedicineNathan Kline InstituteInstitut de Génomiqueénomique Fonctionnelle, Université de Montpellier, INSERM, CNRSAbstract Aberrant cortisol and activation of the glucocorticoid receptor (GR) play an essential role in age-related progression of Alzheimer's disease (AD). However, the GR pathways required for influencing the pathobiology of AD dementia remain unknown. To address this, we studied an early phase of AD-like progression in the well-established APP/PS1 mouse model combined with targeted mutations in the BDNF-dependent GR phosphorylation sites (serines 134/267) using molecular, behavioral and neuroimaging approaches. We found that disrupting GR phosphorylation (S134A/S267A) in mice exacerbated the deleterious effects of the APP/PS1 genotype on mortality, neuroplasticity and cognition, without affecting either amyloid-β deposition or vascular pathology. The dynamics, maturation and retention of task-induced new dendritic spines of cortical excitatory neurons required GR phosphorylation at the BDNF-dependent sites that amyloid-β compromised. Parallel studies in postmortem human prefrontal cortex revealed AD subjects had downregulated BDNF signaling and concomitant upregulated cortisol pathway activation, which correlated with cognitive decline. These results provide key evidence that the loss of neurotrophin-mediated GR phosphorylation pathway promotes the detrimental effects of the brain cortisol response that contributes to the onset and/or progression of AD dementia. These findings have important translational implications as they provide a novel approach to treating AD dementia by identifying drugs that increase GR phosphorylation selectively at the neurotrophic sites to improve memory and cognition.https://doi.org/10.1186/s40478-022-01396-7Glucocorticoid receptorBDNFMemoryNeuroimagingSpine dynamics |
| spellingShingle | Yann Dromard Margarita Arango-Lievano Amelie Borie Maheva Dedin Pierre Fontanaud Joan Torrent Michael J. Garabedian Stephen D. Ginsberg Freddy Jeanneteau Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway Acta Neuropathologica Communications Glucocorticoid receptor BDNF Memory Neuroimaging Spine dynamics |
| title | Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway |
| title_full | Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway |
| title_fullStr | Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway |
| title_full_unstemmed | Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway |
| title_short | Loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid-β pathway |
| title_sort | loss of glucocorticoid receptor phosphorylation contributes to cognitive and neurocentric damages of the amyloid β pathway |
| topic | Glucocorticoid receptor BDNF Memory Neuroimaging Spine dynamics |
| url | https://doi.org/10.1186/s40478-022-01396-7 |
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