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Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503. Epub 2010 Mar 15 PubMed.
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College of Medicine, University of Arizona
I suggest reading the excellent Alzforum news article by Tom Fagan on our findings regarding the efficacy of allopregnanolone to reverse neurogenic and cognitive deficits in the 3xTgAD male mouse in PNAS and hyperphosphorylated tau in neural progenitor cells reported by Orly Lazarov and colleagues.
Universidad Autónoma de Madird
We have previously published that doublecortin positive cells also express hyperphosphorylated tau (Fuster-Matanzo et al., 2009). Thus, we demonstrated that new neurons generated in the subgranular zone express tau in a hyperphosphorylated form. Phospho-tau expression colocalized with doublecortin but not with glial fibrillary acidic protein, Ki67 or calbindin. The same was observed in the subventricular zone. Tau knockout mice did not show a significant decrease in the number of doublecortin-positive cells, although a deficit in migration was observed. These findings suggest that tau phosphorylation in doublecortin-positive cells is involved in normal migration of new neurons.
References:
Fuster-Matanzo A, de Barreda EG, Dawson HN, Vitek MP, Avila J, Hernández F. Function of tau protein in adult newborn neurons. FEBS Lett. 2009 Sep 17;583(18):3063-8. PubMed.
View all comments by Felix HernandezUniversity of Goettingen
Whether or not physical activity and/or enriched environment could have a potential therapeutic effect in patients with Alzheimer disease (AD) is usually assessed in transgenic mouse models. There is no doubt that in wild-type mice, both physical activity and enriched environment lead to increased neurogenesis in some brain areas, e.g., the dentate gyrus. In contrast, the situation is much less clear in APP transgenic mouse models.
In a recent study, we analyzed neurogenesis in APP/PS1KI mice and quantified the number of doublecortin (DCX)-positive neurons in the subgranular zone of the dentate gyrus (Cotel et al., 2010). Already at the age of two months, a significantly reduced number of DCX-positive neurons were detected in APP/PS1KI mice compared to age-matched wild-type mice. This is the time point when the first amyloid plaques become apparent. In good agreement with a previous study (Faure et al., 2009), neurogenesis was almost completely absent by the age of six months. Interestingly, this loss of neurogenesis could not be modified by keeping the mice in an enriched environment for a four-month period (from two to six months), although a significant increase in the number of DCX-positive neurons was detected in wild-type mice, underscoring the validity of the enrichment paradigm. Moreover, neuron loss in the CA1 region of the hippocampus of six-month-old APP/PS1KI mice (Breyhan et al., 2009) was not ameliorated by four months of enriched housing.
It is difficult to draw clear-cut conclusions for the human situation as environmental enrichment produced variable outcomes, probably due to differences in the AD mouse models that have been previously studied. The APP/PS1KI model represents a model for mild to severe AD. It shows early behavioral deficits starting at two months of age with fast deterioration. Therefore, our data might suggest that physical activity and enriched environment may only be beneficial in patients with mild cognitive impairment (or even earlier, before symptoms appear) and not in patients with early AD.
References:
Cotel MC, Jawhar S, Christensen DZ, Bayer TA, Wirths O. Environmental enrichment fails to rescue working memory deficits, neuron loss, and neurogenesis in APP/PS1KI mice. Neurobiol Aging. 2012 Jan;33(1):96-107. PubMed.
Faure A, Verret L, Bozon B, El Tannir El Tayara N, Ly M, Kober F, Dhenain M, Rampon C, Delatour B. Impaired neurogenesis, neuronal loss, and brain functional deficits in the APPxPS1-Ki mouse model of Alzheimer's disease. Neurobiol Aging. 2011 Mar;32(3):407-18. PubMed.
Breyhan H, Wirths O, Duan K, Marcello A, Rettig J, Bayer TA. APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy. Acta Neuropathol. 2009 Jun;117(6):677-85. PubMed.
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