Effects Of DHEA On Aβ_25-35 -impaired Neurogenesis In The Dentate Gyrus And The Underlying Mechanisms

Effects of DHEA on Aβ_25-35-impaired neurogenesis in the dentate gyrus and the underlying mechanismsINTRODUCTIONProgenitor cells in the hippocampal dentate gyrus (DG) retain ability to proliferate and a significant number of daughter cells develop into neurons in adult mammalian species. The newborn neurons, similar to the established ones, are electrically active and make connections to the hippocampal CA3 field, suggesting that they are functional. This is reinforced by evidence that hippocampus-dependent memory is strongly correlated with increased levels of newborn neurons, while the inhibition of neurogenesis has adverse effects on cognitive behaviors. Thus, hippocampal neurogenesis in adult animals has been implicated to contribute, at least in part, to learning and memory.Alzheimer's disease (AD) is characterized byβ-amyloid (Aβ) deposition and a progressive loss of neurons leading to dementia. In an AD model of over-expressing Aβ, increasing evidence indicates that overproduction of Aβand consequent appearance of amyloid plaques dramatically diminish the survival of newborn cells, leading to a long-lasting impairment in hippocampal neurogenesis. Consistent with an earlier study, we in the present study have observed that intracerebroventricular injection of Aβ_25-35 (3 nmol) to adult male mice stimulates endogenous proliferation of progenitor cells in the DG, but the newborn cells will die in 7-14 days after birth. Thus, it is suggested that the reduced capability of hippocampal neuron replacement may contribute, at least in part, to the cognitive deficiency in AD.Levels of dehydroepiandrosterone (DHEA) in the central nervous system are generally higher than those in serum and this trend remains even after adrenalectomy. In clinical studies, the formation of plaques and neurofibrillary tangles are correlated with the decreased brain levels of DHEA sulfate, suggesting a possible neuroprotective effect of the neurosteroid in AD. An earlier study reported that the treatment with DHEA could ameliorate the Aβ_25-35-induced deficits in memory function. In particular, DHEA enhances the axonal and dendritic growth in neurons, and induces spine synapse formation. In addition, DHEA is able to promote neuronal survival of human neural stem cells. Successive interaction of newborn neurons in the DG with hilar mossy cells, interneurons, and CA3 pyramidal neurons might contribute differentially to target-dependent cell survival. The Aβ_25-35-infusion results in a large amount of death of the newborn neurons in the 2nd week after birth, a critical period of their neurite growth. Thus, it should be interesting to explore whether DHEA improves the Aβ_25-35-induced death of newborn neurons in the adult DG.DHEA has been identified to be a potent agonist for sigma 1 (σ1) receptor. Activation ofσ1 receptor enhances Ca2+ influx across NMDA receptor and increases the inositol-1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ efflux from ER pools. Activation ofσ1 receptor also enhances the NGF-induced neurite outgrowth through modulating the PLCγ-DAG-PKC, Ras-Raf-MEK-ERK and PI3K-Akt-mTOR signaling pathways. Recently, much attention has been attracted to an Aβinterruption of the PI3K-Akt-mTOR signaling that is important for the neuronal differentiation of neural progenitor cells and the embryonic development. The dysfunction of mTOR results in death of mouse embryos.OBJECTIVEThe aims of the present study were to investigate the effects of DHEA on the Aβ_25-35-impaired survival of newborn neurons in the hippocampal DG, and to explore the underlying molecular mechanisms.MATERIALS AND METHODS1. Preparation of an animal model: Aβ_25-35 is the shortest fragment of the Aβprocessed in vivo by brain proteases.2. Drug administration: Proliferating cells were labeled by bromodeoxyuridine (BrdU). DHEA, DHEAS, PREG and TE at 20 mg/kg concentration were injected (i.p.) once daily. PRE084, rapamycin, NE100 were injected (i.p.). U0126, 2-APB, LY294002, chelerythrine chloride were infused into the cereboventricle (i.c.v.).3. Immunohistochemistry: BrdU and Doublecortin immuno-reactivities were visualized by avidin-biotin horseradish peroxidase complex. Hoechst staining with hoechst-33342.4. Western blot analysis: ERK1/2, Akt, mTOR or p70s6k.5. Behavioral Analysis: Morris water maze task.RESULTS1. Aβ_25-35 stimulates cell proliferation but impairs survival of newborn neurons in the DG.2. Aβ_25-35 impairs neurite growth of newborn neurons.3. DHEA prevents Aβ_25-35-impaired survival of newborn neurons.4.σ1 receptor is involved in DHEA-protection against Aβ_<sub>25-35-impaired survival of newborn neurons.5. Activations of PI3K and mTOR are required for DHEA-neuroprotection.6. DHEA prevents Aβ_25-35-impaired PI3K-Akt-mTOR-p70s6k signaling pathway.7. DHEA prevents Aβ_25-35-impaired neurite growth of newborn neurons. CONCLUSION The present study for the first time provides in vivo evidence that a treatment with DHEA prevents Aβ_25-35-impaired survival of newborn neurons through aσ1 receptor-mediated modulation of PI3K-Akt-mTOR-p70s6k signaling.CLINIC SIGNIFICANCEOf great importance in this study is that the treatment with DHEA improves the poor survival of newborn neurons in Aβ_25-35-tretaed mice. An earlier study reported that the treatment with DHEA could ameliorate the cognitive deficits in Aβ_25-35-infused mice. Although the results in the present study do not provide direct evidence that the DHEAincreased newborn neurons in the DG contributes to improve the Aβ_25-35-induced deficits in learning and memory, a strong correlation between the enhanced survival of newborn neurons and the spatial memory has been demonstrated in adult male mice. It would be critically important to investigate whether the DHEA-increased newborn neurons will be integrated into hippocampal neuronal circuitry and contribute to the improvement in leaning and memory in adult animals.