Abstract
Neurogenesis is a life long process, but the rate of cell proliferation and differentiation decreases with age. In Alzheimer's patients, along with age, the presence of Aβ in the brain inhibits this process by reducing stem cell proliferation and cell differentiation. GLP-1 is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and the GLP-1 analogue liraglutide has been shown to increase cell proliferation in an Alzheimer's disease (AD) mouse model. Here we investigated acute and chronic effects of liraglutide on progenitor cell proliferation, neuroblast differentiation and their subsequent differentiation into neurons in wild type and APP/PS-1 mice at different ages. APP/PS1 and their littermate controls, aged 3, 6, 12, 15 months were injected acutely or chronically with 25 nmol/kg liraglutide. Acute treatment with liraglutide showed an increase in cell proliferation in APP/PS1 mice, but not in controls whereas chronic treatment increased cell proliferation at all ages (BrdU and Ki67 markers). Moreover, numbers of immature neurons (DCX) were increased in both acute and chronic treated animals at all ages. Most newly generated cells differentiated into mature neurons (NeuN marker). A significant increase was observed with chronically treated 6, 12, 15 month APP/PS1 and WT groups. These results demonstrate that liraglutide, which is currently on the market as a treatment for type 2 diabetes (VictozaTM), increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD.
Highlights
Adult neurogenesis is a process of continuous generation of new neurons and glia cells from neuronal progenitor/stem cell (NSC), which incorporates in existing circuitry [1]
Neurogenesis in the mammalian brain arises from the subventricular zone (SVZ) in the lateral ventricles, and the subgranular zone (SGZ) in the hippocampal dentate gyrus [2,3,4]
The new neurons have shown to extend their axonal projections into the hippocampal CA3 area [46], indicating that they play a functional role in the neuronal network of the hippocampus
Summary
Adult neurogenesis is a process of continuous generation of new neurons and glia cells from neuronal progenitor/stem cell (NSC), which incorporates in existing circuitry [1]. Neurogenesis in the mammalian brain arises from the subventricular zone (SVZ) in the lateral ventricles, and the subgranular zone (SGZ) in the hippocampal dentate gyrus [2,3,4]. Factors regulating adult neurogenesis include stress, age, inflammation processes and drugs [6,7,8,9]. A decrease in hippocampal neurogenesis is a natural ageing process [10,11], which is exacerbated in pathological conditions like Parkinson’s and Alzheimer’s disease AD [12,13]. There is the potential that the normalisation of stem cell proliferation in the brain may be of benefit in treating neurodegenerative diseases, and this area of research has been a focus point [14,15,16,17]
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