Final Activity Report Summary - ASBANSC (Interactions between adrenal steroids and beta amyloid in the regulation of neural stem cells)
In this project, we investigated the interactions between amyloid-beta1-42 (Abeta1-42), corticosterone and dehydroepiandrosterone (DHEA) on various aspects of hippocampal neurogenesis. Specifically, we explored the influences of Abeta1-42 and adrenal steroids (corticosterone and DHEA) on the proliferation, survival and migration of newly born hippocampal cells both in vitro (using neural stem/neuroprogenitor cells (NS/PCs)) isolated from hippocampi of 10 day old C56BL6J mice) and in vivo, either in normal (eight-month old female C57BL6J mice) or pathological brains (TASTPM mice, a transgenic model of Alzheimer's disease).
Our in vivo results indicate that corticosterone significantly affects adult hippocampal neurogenesis in female C57BL6J mice, reducing the total number of BrdU- (dividing cells) and doublecortin - labelled cells (cells differentiating towards a neuronal phenotype). Corticosterone also significantly inhibited the differentiation of newly formed hippocampal cells, reducing the percentage of BrdU/DCX double - labelled cells. Unexpectedly, we found that corticosterone-mediated effects were attenuated in female TASTPM mice and in contrast to published results, DHEA showed negligible effects on adult hippocampal neurogenesis.
In vitro data appear to support and strengthen corticosterone in vivo findings. Corticosterone exposure was associated with a significant, concentration-dependent suppression of NS/PC proliferation and survival while contrary to previously published data regarding its deleterious effects on neurons, Abeta1-42 was associated with negligible effects on proliferation but significant enhancement of NS/PC viability. Remarkably, Abeta1-42 attenuated glucocorticoid-mediated effects on both proliferation and viability of NSCs/NPCs.
Finally, while corticosterone exposure resulted in a significant reduction of NSC/NPC migration, Abeta1-42 appeared to promote it, attenuating corticosterone-mediated actions. In contrast to in vivo data however, DHEA enhanced NS/PC proliferation at low concentrations with an opposite effect at high levels. Interestingly, DHEA also attenuated the inhibition of NS/PC proliferation associated with exposure to high corticosterone concentrations.These findings provide new evidence to support the inhibitory influences of glucocorticoids on adult hippocampal neurogenesis. More importantly, they seem to illustrate a dual role for Abeta1-42. Despite being a key factor in the sequence of events leading to neurodegeneration in Alzheimer's disease, these results now suggest a protective effect of Abeta1-42 against the detrimental effects of glucocorticoids on hippocampal neurogenesis.
In this project we also investigated effects of aging on adult hippocampal neurogenesis. Throughout life (of a rodent), hippocampal neurogenesis declines steadily over the first few months, yet this form of neuroplasticity persists into senescence despite a dramatic drop in the number of neurons it produces.Although it is well established that neurogenesis slows with age, it is unclear whether this change is due to a deceleration of the cell cycle, as occurs during development, or a loss of precursor cells. We provide evidence to indicate that aging, at least until 12 months of age, does not significantly alter the total number of SOX1-labeled cells in the subgranular zone of the hippocampus, a neurogenic region where new cells (glial and neuronal) continue to be generated throughout life, despite remarkably reducing the number of BrdU- and DCX-labelled cells. These results suggest that the reduction of neurogenesis observed with aging is most likely linked to a slowing down of the cell cycle rather than a loss of precursor cells.
Our in vivo results indicate that corticosterone significantly affects adult hippocampal neurogenesis in female C57BL6J mice, reducing the total number of BrdU- (dividing cells) and doublecortin - labelled cells (cells differentiating towards a neuronal phenotype). Corticosterone also significantly inhibited the differentiation of newly formed hippocampal cells, reducing the percentage of BrdU/DCX double - labelled cells. Unexpectedly, we found that corticosterone-mediated effects were attenuated in female TASTPM mice and in contrast to published results, DHEA showed negligible effects on adult hippocampal neurogenesis.
In vitro data appear to support and strengthen corticosterone in vivo findings. Corticosterone exposure was associated with a significant, concentration-dependent suppression of NS/PC proliferation and survival while contrary to previously published data regarding its deleterious effects on neurons, Abeta1-42 was associated with negligible effects on proliferation but significant enhancement of NS/PC viability. Remarkably, Abeta1-42 attenuated glucocorticoid-mediated effects on both proliferation and viability of NSCs/NPCs.
Finally, while corticosterone exposure resulted in a significant reduction of NSC/NPC migration, Abeta1-42 appeared to promote it, attenuating corticosterone-mediated actions. In contrast to in vivo data however, DHEA enhanced NS/PC proliferation at low concentrations with an opposite effect at high levels. Interestingly, DHEA also attenuated the inhibition of NS/PC proliferation associated with exposure to high corticosterone concentrations.These findings provide new evidence to support the inhibitory influences of glucocorticoids on adult hippocampal neurogenesis. More importantly, they seem to illustrate a dual role for Abeta1-42. Despite being a key factor in the sequence of events leading to neurodegeneration in Alzheimer's disease, these results now suggest a protective effect of Abeta1-42 against the detrimental effects of glucocorticoids on hippocampal neurogenesis.
In this project we also investigated effects of aging on adult hippocampal neurogenesis. Throughout life (of a rodent), hippocampal neurogenesis declines steadily over the first few months, yet this form of neuroplasticity persists into senescence despite a dramatic drop in the number of neurons it produces.Although it is well established that neurogenesis slows with age, it is unclear whether this change is due to a deceleration of the cell cycle, as occurs during development, or a loss of precursor cells. We provide evidence to indicate that aging, at least until 12 months of age, does not significantly alter the total number of SOX1-labeled cells in the subgranular zone of the hippocampus, a neurogenic region where new cells (glial and neuronal) continue to be generated throughout life, despite remarkably reducing the number of BrdU- and DCX-labelled cells. These results suggest that the reduction of neurogenesis observed with aging is most likely linked to a slowing down of the cell cycle rather than a loss of precursor cells.