PLA2G4E, a candidate gene for resilience in Alzheimer´s disease and a new target for dementia treatment
| Autor: | Maria Espelosin, Diego Sucunza, Marta Pérez-González, Mar Cuadrado-Tejedor, Susana Ursua, Rafael Luján, Sara Badesso, Miren Roldan, Maite Mendioroz, Ana Garcia-Osta |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Candidate gene Dendritic spine Amyloid Genetic enhancement Dendritic Spines Mice Transgenic Disease Hippocampal formation Hippocampus 03 medical and health sciences Mice 0302 clinical medicine Alzheimer Disease mental disorders medicine Dementia Animals Humans Spatial Memory Behavior Animal business.industry General Neuroscience Group IV Phospholipases A2 Cognition Genetic Therapy medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Gene Expression Regulation Female business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Progress in neurobiology. 191 |
| ISSN: | 1873-5118 |
| Popis: | Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2G4E overexpressing APP/PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits. |
| Databáze: | OpenAIRE |
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