Cell-autonomous and non-cell autonomous effects of neuronal BIN1 loss in vivo
| Autor: | Jake Gagnon, Michael Peterson, Prescott Leach, Chris Roberts, Andrea Crotti, Hameetha Banu Rajamohamed Sait, Galina Marsh, Taylor L. Reynolds, Sarah Geisler, Kathleen M. McAvoy, Richard M. Ransohoff, Ellen Cahir-McFarland |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Apolipoprotein E Gene Expression Endogeny Alzheimer's Disease Hippocampus Transcriptome Small hairpin RNA Mice 0302 clinical medicine Animal Cells Medicine and Health Sciences Mice Knockout Neurons Mammals Multidisciplinary Behavior Animal Microglia Brain Eukaryota Neurodegenerative Diseases Animal Models Genomics Cell biology medicine.anatomical_structure Experimental Organism Systems Neurology Vertebrates Medicine Female Cellular Types Anatomy Transcriptome Analysis Research Article Gene isoform Science Nerve Tissue Proteins tau Proteins Glial Cells Mouse Models Biology Research and Analysis Methods Rodents 03 medical and health sciences Model Organisms Atrophy Alzheimer Disease In vivo Mental Health and Psychiatry Genetics medicine Animals Microglial Cells Adaptor Proteins Signal Transducing Gene Expression Profiling Tumor Suppressor Proteins Organisms Biology and Life Sciences Computational Biology Cell Biology Genome Analysis medicine.disease Rats Mice Inbred C57BL Disease Models Animal 030104 developmental biology nervous system Cellular Neuroscience Amniotes Animal Studies Dementia Biomarkers 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE, Vol 14, Iss 8, p e0220125 (2019) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | BIN1 is the most important risk locus for Late Onset Alzheimer’s Disease (LOAD), after ApoE. BIN1 AD-associated SNPs correlate with Tau deposition as well as with brain atrophy. Furthermore, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases in parallel with neuronal loss, despite an overall increase in BIN1 total mRNA. To address the relationship between reduction of BIN1 and neuronal cell loss in the context of Tau pathology, we knocked-down endogenous murine Bin1 via stereotaxic injection of AAV-Bin1 shRNA in the hippocampus of mice expressing Tau P301S (PS19). We observed a statistically significant reduction in the number of neurons in the hippocampus of mice injected with AAV-Bin1 shRNA in comparison with mice injected with AAV control. To investigate whether neuronal loss is due to deletion of Bin1 selectively in neurons in presence Tau P301S, we bred Bin1flox/flox with Thy1-Cre and subsequently with PS19 mice. Mice lacking neuronal Bin1 and expressing Tau P301S showed increased mortality, without increased neuropathology, when compared to neuronal Bin1 and Tau P301S-expressing mice. The loss of Bin1 isoform 1 resulted in reduced excitability in primary neurons in vitro, reduced neuronal c-fos expression as well as in altered microglia transcriptome in vivo. Taken together, our data suggest that the contribution of genetic variation in BIN1 locus to AD risk could result from a cell-autonomous reduction of neuronal excitability due to Bin1 decrease, exacerbated by the presence of aggregated Tau, coupled with a non-cell autonomous microglia activation. |
| Databáze: | OpenAIRE |
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