Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTgAD and nonTg mice

Neuroscience Program, University of Southern California, Los Angeles, CA 90089-9121, USA.
Neurobiology of aging (Impact Factor: 5.01). 07/2011; 33(8):1493-506. DOI: 10.1016/j.neurobiolaging.2011.06.008
Source: PubMed


We previously demonstrated that allopregnanolone (APα) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.B., Ball, B.G., Brinton, R.D., 2005. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718; Wang, J.M., Singh, C., Liu, L., Irwin, R.W., Chen, S., Chung, E.J., Thompson, R.F., Brinton, R.D., 2010. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 107, 6498-6503). Herein, we determined efficacy of APα to restore neural progenitor cell survival and associative learning and memory subsequent to AD pathology in male 3xTgAD mice and their nontransgenic (nonTg) counterparts. APα significantly increased survival of bromodeoxyuridine positive (BrdU+) cells and hippocampal-dependent associative learning and memory in 3xTgAD mice in the presence of intraneuronal amyloid beta (Aβ) whereas APα was ineffective subsequent to development of extraneuronal Aβ plaques. Restoration of hippocampal-dependent associative learning was maximal by the first day and sustained throughout behavioral training. Learning and memory function in APα-treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, APα significantly increased survival of bromodeoxyuridine-positive cells and hippocampal-dependent associative learning and memory. Results provide preclinical evidence that APα promoted survival of newly generated cells and restored cognitive performance in the preplaque phase of AD pathology and in late-stage normal aging.

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    • "Singh et al in 2011 followed up with a study showing that allopregnanolone (10 mg/kg s.c.) effectively influenced trace eye‐blink conditioning in 6 and 9 month old 3xTgAD mice, but not in the 12 month old AD mice. Contrary, in 15 month old non‐ transgenic mice decreased learning of trace eye‐blink conditioning and decreased neurogenesis was rescued by one allopregnanolone treatment (Singh et al., 2012). "
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    • "In mice lesioned with MPTP, APα reversed the cell number decline of TH-expressing and Nissl positive cells in both SN and Locus coeruleus (LC; Adeosun et al., 2012). This data suggest that the generation of new cells by APα is not cell type, brain region, or mouse model specific, as we previously reported the neurogenic property of APα in the SGZ and SVZ in a mouse model of AD (Wang et al., 2010; Chen et al., 2011; Singh et al., 2012). The fact that APα increased the proliferation of cerebellar neurogenic cells supports the observation that APα is not only a neurogenic agent in known neurogenic areas such as SGZ and SVZ, but also in brain regions such as the cerebellum (Keller et al., 2004) and the SNpc (Adeosun et al., 2012; Sun et al., 2012a). "
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    • "Increased hippocampal neurogenesis, increase neural progenitor cell survival, and reverse learning and memory deficits, decreased microglial activation, and decreased amyloid-beta pathology (Brinton, 1994, 2013; Wang et al., 2010; Irwin et al., 2011; Singh et al., 2012; Lo et al., 2014). "
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