Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease
Open Access
- 15 March 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (14), 6498-6503
- https://doi.org/10.1073/pnas.1001422107
Abstract
Our previous analyses showed that allopregnanolone (APα) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APα to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between APα-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. APα significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. APα reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APα-induced survival of neural progenitors was significantly correlated with APα-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Aβ, may contribute to the cognitive phenotype of AD, and that APα could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.Keywords
This publication has 42 references indexed in Scilit:
- GABA-cAMP Response Element-Binding Protein Signaling Regulates Maturation and Survival of Newly Generated Neurons in the Adult HippocampusJournal of Neuroscience, 2009
- Fate plasticity of adult hippocampal progenitors: biological relevance and therapeutic useTrends in Pharmacological Sciences, 2009
- Computational Influence of Adult Neurogenesis on Memory EncodingNeuron, 2009
- Allopregnanolone-induced rise in intracellular calcium in embryonic hippocampal neurons parallels their proliferative potentialBMC Neuroscience, 2008
- Aβ Oligomers Induce Neuronal Cell Cycle Events in Alzheimer's DiseaseJournal of Neuroscience, 2008
- Impaired Adult Neurogenesis in the Dentate Gyrus of a Triple Transgenic Mouse Model of Alzheimer's DiseasePLOS ONE, 2008
- Neurons born in the adult dentate gyrus form functional synapses with target cellsNature Neuroscience, 2008
- Neurogenesis, learning and associative strengthEuropean Journal of Neuroscience, 2008
- Progesterone receptors: Form and function in brainFrontiers in Neuroendocrinology, 2008
- Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampusNeurobiology of Aging, 2008