Allopregnanolone increases the number of dopaminergic neurons in substantia nigra of a triple transgenic mouse model of Alzheimer's disease.

TitleAllopregnanolone increases the number of dopaminergic neurons in substantia nigra of a triple transgenic mouse model of Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2012
AuthorsSun C, Ou X, Farley JM, Stockmeier C, Bigler S, Brinton RDiaz, Wang JMing
JournalCurr Alzheimer Res
Volume9
Issue4
Pagination473-80
Date Published2012 May
ISSN1875-5828
KeywordsAlzheimer Disease, Amyloid beta-Protein Precursor, Analysis of Variance, Anesthetics, Animals, Bromodeoxyuridine, Cell Count, Disease Models, Animal, Dopaminergic Neurons, Humans, Mice, Mice, Transgenic, Mutation, Pregnanolone, Presenilin-1, Substantia Nigra, tau Proteins, Tyrosine 3-Monooxygenase
Abstract

More than a third of Alzheimer's disease (AD) patients show nigrostriatal pathway disturbances, resulting in akinesia (inability to initiate movement) and bradykinesia (slowness of movement). The high prevalence of this dysfunction of dopaminergic neuron in the nigrostriatal pathway in AD suggests that the risk factors for AD appear also significant risk factors for substantia nigra pars compacta (SNpc) lesions. Previously, we have demonstrated that allopregnanolone (APα) promotes neurogenesis and improves the cognitive function in a triple transgenic mouse model of AD (3xTgAD). In this study, we sought to exam 1) the SNpc lesions in 3xTgAD mice and 2) the impact of APα on promoting the regeneration of new dopaminergic neurons in SNpc of the 3xTgAD mice. The number of Nissl-stained total neurons, tyrosine hydroxylase (TH) positive neurons, and BrdU/TH double positive newly formed neurons were analyzed with unbiased stereology. In the SNpc of 3xTgAD mice, TH positive neurons was 47+- 18 % (p = 0.007), total neurons was 62 +-11.6 % (p = 0.016), of those in the SNpc of non-Tg mice, respectively. APα treatment increased the TH positive neurons in the SNpc of 3xTgAD mice to 93.2 +- 18.5 (p = 0.021 vs. 3xTgAD vehicle) and the total neurons to 84.9+- 6.6 (p = 0.046 vs. 3xTgAD vehicle) of non-Tg mice. These findings indicate that there is a loss of neurons, specifically the TH positive neurons in SNpc of 3xTgAD mice, and that APα reverses the lesion in SNpc of 3xTgAD by increasing the formation of new TH neurons.

Alternate JournalCurr Alzheimer Res
PubMed ID22272610
PubMed Central IDPMC3348519
Grant ListP20 RR017701 / RR / NCRR NIH HHS / United States
P20 RR017701-09 / RR / NCRR NIH HHS / United States
RR17701 / RR / NCRR NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D