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.

Download full-text


Available from: Ronald Irwin,
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: GABAA receptor modulating steroid antagonists (GAMSA) selectively inhibit neurosteroid-mediated enhancement of GABA-evoked currents at the GABAA receptor. 3α-hydroxy-neurosteroids, notably allopregnanolone and tetrahydrodeoxycorticosterone (THDOC), potentiate GABAa receptor-mediated currents. On the contrary, various 3β-hydroxy-steroids antagonize this positive neurosteroid-mediated modulation. Importantly, GAMSAs are specific antagonists of the positive neurosteroid-modulation of the receptor and do not inhibit GABA-evoked currents.
    The Journal of steroid biochemistry and molecular biology 11/2015; DOI:10.1016/j.jsbmb.2015.10.019 · 3.63 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Reinstalling the neurobiological circuits to effectively change the debilitating course of neurodegenerative diseases is of utmost importance. This reinstallation requires generation of new cells which are able to differentiate into specific types of neurons and modification of the local environment suitable for integration of these new neurons into the neuronal circuits. Allopregnanolone (APα) seems to be involved in both of these processes, and therefore, is a potential neurotrophic agent. Loss of dopamine neurons in the substantia nigra (SN) is one of the main pathological features of Parkinson's and also in, at least, a subset of Alzheimer's patients. Therefore, reinstallation of the dopamine neurons in nigrostriatal tract is of unique importance for these neurodegenerative diseases. However, for the neurogenic status and the roles of allopregnanolone in the nigrostriatal tract, the evidence is accumulating and debating. This review summarizes recent studies regarding the neurogenic status in the nigrostriatal tract. Furthermore, special attention is placed on evidence suggesting that reductions in allopregnenalone levels are one of the major pathological features in PD and AD. This evidence has also been confirmed in brains of mice that were lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or those bearing neurodegenerative mutations. Lastly, we highlight studies showing that allopregnanalone can augment the number of total cells and dopaminergic neurons via peripheral exogenous administration.
    Frontiers in Cellular Neuroscience 08/2014; 8:224. DOI:10.3389/fncel.2014.00224 · 4.29 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Allopregnanolone (Allo), a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer’s disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer’s pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer’s mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer’s, Parkinson’s, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer’s disease that have the potential to accelerate therapeutic translation for multiple unmet neurological needs.
    Frontiers in Cellular Neuroscience 07/2014; 8:203. DOI:10.3389/fncel.2014.00203 · 4.29 Impact Factor
Show more