Impact Of Neurosteroids PREGS And DHEA On The Neurogenesis In Alzheimer's Disease

IntroductionIt is widely accepted that the mammalian brain produces continuously newborn neurons in the hippocampal dentate gyrus (DG) throughout the adult life with a comparative rate as that of mature granular cells death. It has been implicated that the adult hippocampal neurogenesis plays an important role in the regulation of cognition. Hippocampal neurogenesis decreases drastically during aging in rodents, and this decline in neurogenic capacity has been suggested to underlie cognitive deterioration in aged animals. Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by selective damage in the cognitive function. The number of immature newborn neurons is increased in the hippocampus of AD patients and model with Swedish and Indiana amyloid precursor protein mutations. It is also known that the overproduction and subsequent aggregation of Aβlimit the survival of hippocampal newborn neurons. Thus, it is speculated that the impaired hippocampal neurogenesis might be one of the causes for cognitive deterioration in AD.Neurosteroids dehydroepiandrosterone (DHEA) and pregnenolone sulfate (PREGS) are synthesized in the rodent brain independently of peripheral glandular sources. Previous study reported that DHEA could increase the number of newly generated neurons in rat hippocampal dentate gyrus and antagonize the suppressive effect of corticosterone on neuronal precursor proliferation. PREGS is also known to facilitate the production of new neurons, which takes place during early development and throughout life within specific brain regions such as the dentate gyrus of the hippocampus. Specially, PREGS influences the developmental processes of neural circuit formation through strengthening immature excitatory synapses in the hippocampus. Even in old rats, PREGS stimulates neurogenesis in the dentate gyrus. Recently, correlation between the decreased level of brain neurosteroids and neuronal degeneration in AD patients has been paid close attention. Interestingly, the level of DHEA increases in AD patients, although synthesis of brain DHEA declines with normal aging. The level of PREGS decreases in AD patients'brain in comparison with that of age-matched non-demented controls.Objective(1) To determine the changes in the hippocampal neurogenesis in male mice over-expressing amyloid precursor protein (APP) and presenilin-1 (PS1) (APP/PS1 mice).(2) To explore the effects of neurosteroids PREGS or DHEA on neurogenesis and the impairment of spatial memory in APP/PS1 mice.Materials and Methods1. Preparation of an animal model: APP/PS1 mice were obtained from Jackson Laboratory (Bar Harbor, ME, USA). The genotyping for APP/PS1 mice was performed by polymerase chain reaction (PCR) method recommended by the Jackson Laboratory, using tissue samples from tail of mice. The APP/PS1 mice were generated by crossing transgenic mice with B6C3F1 mice and characterized as described previously.2. Drug administration: Proliferating cells were labeled by bromodeoxyuridine (BrdU). DHEA and PREGS at 20 mg/kg concentration were injected (i.p.) once daily.3. Immunohistochemistry: Aβ,Ki67,BrdU and Doublecortin immuno-reactivities were visualized by avidin-biotin horseradish peroxidase complex. BrdU and NeuN or GFAP double immunostaining. And quantitative evaluation of immuno-positive cells. 4. Behavioral Analysis: Morris water maze task.Results1,8-month-old APP/PS1 mice showed the extracellular deposition of Aβ, amyloid plaques in hippocampus and spatial memory impairment2,Comparison with control rats, in the hippocampal dentate gyrus of 8-month-old APP/PS1 mice the proliferation of progenitor cells increased, while the neurite growth and survival of newborn neuronal cells were markedly impaired.3,Either PREGS or DHEA could perfectly rescue the hypoplastic neurite of newborn neurons in APP/PS1 mice, whereas neither of them affected the over-proliferation of progenitor cells.4,Notably, PREGS but not DHEA could protect the survival of newborn neuronal cells to approach maturation in APP/PS1 mice.5,The protection of hippocampal neurogenesis in APP/PS1 mice treated with PREGS was accompanied with an improvement of spatial learning and memory.ConclusionThe present study provides in vivo evidence that the treatment with either PREGS or DHEA could rescue the impaired neurite of newborn neurons, but only PREGS perfectly protected the survival and maturation of newly generated neuronal cells in APP/PS1 mice. The protection of PREGS against Aβ-impaired neurogenesis had a definite effect on improving cognitive deterioration in APP/PS1 mice.