Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model

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 (Victoza(TM)), increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD.

Figure 1. Quantification of BrdU positive cells in the SGZ of WT and APP/PS1 animals at different ages.

Progenitor cell proliferation in SGZ decreases with age. Values are expressed as mean ± SEM (n = 6). ^***p<0.001 compared with respective controls.

Figure 2. Quantification of BrdU positive cells in the SGZ.

Acute treatment with liraglutide does not increase cell proliferation at any age in wild type animals whereas in APP/PS1 animals treatment with liraglutide increases cell proliferation regardless of age. Quantification of Ki67 positive cells in the SGZ. Acute treatment with liraglutide increases endogenous cell proliferation at all ages in wild type and APP/PS1 animals ^*p<0.05, ^**p<0.01 compared with saline control. Values are expressed as mean ± SEM (n = 6).

Figure 3. Acute treatment with liraglutide significantly increases DCX-immunoreactive cells in the DG of both wild type and APP/PS1 at all ages.

^*p<0.05, ^**p<0.01 compared with saline control. Values are expressed as mean ± SEM (n = 6).

Figure 4. Quantification of BrdU positive cells in the SGZ.

Chronic treatment with liraglutide increases cell proliferation in both wild type and APP/PS1 animals regardless of age. Quantification of Ki67 immunoreactive cells in the SGZ. Chronic treatment with liraglutide increases endogenous cell proliferation in both wild type and APP/PS1 animals regardless of age. ^*p<0.05, ^**p<0.01 compared with saline control. Values are expressed as mean ± SEM (n = 6).

Figure 5. Chronic treatment with liraglutide increases neuroblast differentiation in both wild type and APP/PS1 animals regardless of age.

^*p<0.05, ^**p<0.01 compared with saline control. Values are expressed as mean ± SEM (n = 6).

Figure 6. Chronic treatment with liraglutide significantly increases differentiation of newly produced cells to new neurons in wild type group at 6, 12 and 15 months wild type mice and APP/PS1 mice.

No difference was seen at 3 months of age. No significant difference was seen in newly generated glia cell. ^*p<0.05, ^**p<0.01 compared with saline control. Values are expressed as mean ± SEM (n = 6).