| Autor: |
Jade Marsh, Saifuddien Haji Bagol, Robin S.B. Williams, George Dickson, Pavlos Alifragis |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
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| Zdroj: |
Neurobiology of Disease, Vol 106, Iss , Pp 63-75 (2017) |
| Druh dokumentu: |
article |
| ISSN: |
1095-953X |
| DOI: |
10.1016/j.nbd.2017.06.011 |
| Popis: |
Alzheimer's disease is the most prevalent form of dementia in the elderly but the precise causal mechanisms are still not fully understood. Growing evidence supports a significant role for Aβ42 oligomers in the development and progression of Alzheimer's. For example, intracellular soluble Aβ oligomers are thought to contribute to the early synaptic dysfunction associated with Alzheimer's disease, but the molecular mechanisms underlying this effect are still unclear. Here, we identify a novel mechanism that contributes to our understanding of the reported synaptic dysfunction. Using primary rat hippocampal neurons exposed for a short period of time to Aβ42 oligomers, we show a disruption in the activity-dependent phosphorylation cycle of SynapsinI at Ser9. SynapsinI is a pre-synaptic protein that responds to neuronal activity and regulates the availability of synaptic vesicles to participate in neurotransmitter release. Phosphorylation of SynapsinI at Ser9, modulates its distribution and interaction with synaptic vesicles. Our results show that in neurons exposed to Aβ42 oligomers, the levels of phosphorylated Ser9 of SynapsinI remain elevated during the recovery period following neuronal activity. We then investigated if this effect could be targeted by a putative therapeutic regime using valproic acid (a short branch-chained fatty acid) that has been proposed as a treatment for Alzheimer's disease. Exposure of Aβ42 treated neurons to valproic acid, showed that it restores the physiological regulation of SynapsinI after depolarisation. Our data provide a new insight on Aβ42-mediated pathology in Alzheimer's disease and supports the use of Valproic acid as a possible pharmaceutical intervention for the treatment of Alzheimer's disease. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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Full Text from ScienceDirect