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P4–350: Promotion of neurogenesis in the triple transgenic Alzheimer's mouse dentate gyrus and subventricular zone by the neurosteroid allopregnanolone
Author(s) -
Brinton Roberta D.,
Wang Jun Ming,
Irwin Ronald,
Liu Lifei,
Chen Shuhua,
Wu Tzu-wei
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2091
Subject(s) - subventricular zone , subgranular zone , neurogenesis , dentate gyrus , neural stem cell , progenitor cell , genetically modified mouse , biology , neuroepithelial cell , microbiology and biotechnology , stem cell , endocrinology , medicine , hippocampal formation , transgene , biochemistry , gene
Background: We have previously demonstrated that allopregnanolone (AP ) specifically promotes the rat neural progenitor cells and human cerebral cortical progenitor cell proliferation in vitro. (Wang and Brinton, 2005). Objectives: In this study, we investigated whether AP , a small blood brain permeable neurosteroid, promotes generation of new neurons in vivo by peripheral (s.c.) administration in transgenic 3xTgAD (APPSwe, PS1M146V and tauP301L) and non-Tg mouse models. Methods: The newly formed cells were labeled by BrdU and the samples were evaluated by immunohistochemical and stereological analyses in the subgranular zone (SGZ) of dentate and cerebral subventricular zone (SVZ). Results: Immunohistochemical double labeling demonstrated that the BrdU positive cells were also nestin (a stem cell marker) positive. Results of stereological analyses demonstrated that the basal level of BrdU labeled cells in the dentate gyrus of 3xTgAD mouse was lower than that of non-Tg mice. The lower basal level of proliferation occurred despite the lack of evident AD pathology. AP induced a dose-dependent significant increase of newly formed cells in SGZ of both non-tg and 3xTgAD mouse. AP treatment restored SGZ proliferation to that of control non-Tg mice. Further, AP induced a significant increase in the number of BrdU positive cells in SVZ of 3xTgAD mouse indicating that AP is a proliferative agent for both the SGZ and SVZ neural stem populations. Conclusions: These observations indicate that, in vivo, AP both rescues the neurogenic impairment of 3xTgAD mouse as well as enhancing the proliferative capacity of both the non-Tg and transgenic phenotypes. Results of these analyses suggest that the neurosteroid AP may be an effective neurogenic therapeutic to promote neurogenesis prior to the onset of AD pathology. This work is supported by grants from the Institute for the Study of Aging, the Kenneth T. and Eileen L. Norris Foundation, the L.K. Whittier Foundation and the Stanley Family Trust to RDB.