Abstract
Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers and inflammation. But perhaps more fundamental from a regenerative perspective, are changes in the biochemical milieu of steroid and peptide growth factors, cytokines and neurotransmitter systems. Data from multiple levels of analysis indicate that gonadal steroid hormones and their metabolites can promote neural health whereas their decline or absence are associated with decline in neural health and increased risk of neurodegenerative disease including Alzheimers. Among the steroids in decline, is allopregnanolone (APα), a neurosteroid metabolite of progesterone, which was found to be reduced in the serum [1,2] and plasma [3] and brain of aged vs. young subjects [4]. Further, Alzheimer disease (AD) victims showed an even further reduction in plasma and brain levels of APα relative to age-matched neurologically normal controls [1,4,5]. Our earlier work has shown that AP?? is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex [6]. Our ongoing research seeks to determine the neurogenic potential of APα in the triple transgenic mouse model of Alzheimers disease (3xTgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that neurogenic potential changes with age in nontransgenic mice and that the neurogenic profile differs between non-transgenic and 3xTgAD mice. Comparative analyses indicate that APα modifies neurogenesis in both nontransgenic and 3xTgAD mice. Preliminary data suggest that APα may modify Alzheimers pathology progression. Together the data indicate that APα may maintain the regenerative ability of the brain and modify progression of AD related pathology. Challenges for efficacy of regenerative agents within a degenerative milieu are discussed.
Keywords: Alzheimer disease, dentate gyrus subgranular zone, neural progenitor proliferation, mouse hippocampus, pregnane X receptor
Current Alzheimer Research
Title: Regeneration in a Degenerating Brain: Potential of Allopregnanolone as a Neuroregenerative Agent
Volume: 4 Issue: 5
Author(s): Jun Ming Wang, Ronald W. Irwin, Lifei Liu, Shuhua Chen and Roberta Diaz Brinton
Affiliation:
Keywords: Alzheimer disease, dentate gyrus subgranular zone, neural progenitor proliferation, mouse hippocampus, pregnane X receptor
Abstract: Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers and inflammation. But perhaps more fundamental from a regenerative perspective, are changes in the biochemical milieu of steroid and peptide growth factors, cytokines and neurotransmitter systems. Data from multiple levels of analysis indicate that gonadal steroid hormones and their metabolites can promote neural health whereas their decline or absence are associated with decline in neural health and increased risk of neurodegenerative disease including Alzheimers. Among the steroids in decline, is allopregnanolone (APα), a neurosteroid metabolite of progesterone, which was found to be reduced in the serum [1,2] and plasma [3] and brain of aged vs. young subjects [4]. Further, Alzheimer disease (AD) victims showed an even further reduction in plasma and brain levels of APα relative to age-matched neurologically normal controls [1,4,5]. Our earlier work has shown that AP?? is a neurogenic agent for rodent hippocampal neural progenitors and for human neural progenitor cells derived from the cerebral cortex [6]. Our ongoing research seeks to determine the neurogenic potential of APα in the triple transgenic mouse model of Alzheimers disease (3xTgAD) as AD related pathology progresses from imperceptible to mild to severe. Initial analyses suggest that neurogenic potential changes with age in nontransgenic mice and that the neurogenic profile differs between non-transgenic and 3xTgAD mice. Comparative analyses indicate that APα modifies neurogenesis in both nontransgenic and 3xTgAD mice. Preliminary data suggest that APα may modify Alzheimers pathology progression. Together the data indicate that APα may maintain the regenerative ability of the brain and modify progression of AD related pathology. Challenges for efficacy of regenerative agents within a degenerative milieu are discussed.
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Cite this article as:
Wang Ming Jun, Irwin W. Ronald, Liu Lifei, Chen Shuhua and Brinton Diaz Roberta, Regeneration in a Degenerating Brain: Potential of Allopregnanolone as a Neuroregenerative Agent, Current Alzheimer Research 2007; 4 (5) . https://dx.doi.org/10.2174/156720507783018262
DOI https://dx.doi.org/10.2174/156720507783018262 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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