Brain longevity and its pathologies

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For this last lecture of the year, I'm going to take up a bit on telomeres, the end of the lecture from two weeks ago and then bring everything that was discussed back to memory in order to open up a bit more widely on the integration of the various mechanisms of aging and prepare you for the rest of the lecture, in 2014. I'll start by reminding you of the grain and periglomerular neuron renewal pattern of the olfactory bulb (DIA VI.2). I'll also briefly remind you that aging is accompanied by a decline in the renewal of these cells, accompanied by a parallel decline in telomerase activity (DIA VI.3).

Last week, we began discussing the possible link between telomere shortening and morphological changes in neurons (and not just their senescence and apoptosis). This is important because it suggests another - possibly physiological - function of telomeres. As I had pointed out, it turns out that laboratory mice have much longer telomeres than humans and wild-type mice (40 to 60 kbp versus 5 to 10 kbp). This is why, as you saw last week, analyses are carried out on the^3rd,^4th or^5th generation (G3, G4 or G5) of mice lacking telomerase activity (mutation of Terc, the RNA substrate of telomerase).

The authors (Ferron et al., J. Neurosci. 29: 14394-14407, 2009) point out that as early as G3, there is a drop in the number of GFAP cells (stem cells), neuroblasts and ßIII-tubulin-labeled neurons, plus - as we have also seen previously - a reduction in the volume of the olfactory bulb (DIA VI.4). This same DIA VI.4 recalls the different cell types (NeuN and ßIII-tubulin label the same cells) and the quantitative data in A show the decrease in the number of BrdU-labeled, and therefore newly generated, cells in the olfactory bulb.

Despite this overall decrease in neurogenesis in vivo, neuroblast proliferation as assessed by the number of BrdU-labelled ßIII-tubulin-expressing neurons (injected only 12 h prior to analysis) was identical in WT and mutant at G3 (14.6% versus 11.9% with standard errors of 1.1 and 2.1%, this is in the text not on the DIA). This suggested unaltered proliferation of neuroblasts, but perhaps less subsequent survival of these cells, as suggested by the effect of p53 mutation on cell number in vivo (DIA VI.4 panels A and B) or neurosphere size in vitro (DIA VI.4, panel F).

Indeed, p53 is an anti-oncogene, i.e. a protein that induces senescence and apoptosis (particularly - but not only - in cells at risk of becoming tumoral, hence the term anti-oncogene). Nevertheless, the strongest difference observed by the authors is incomplete differentiation, with a reduction in the length of the longest dendrite and in the number of branches measured by the number of free ends. DIA VI.5 quantifies the percentage of cells differentiated from neurospheres and shows that neurons (ß3-tubulin) are the most affected cells, with rescue by p53 mutation in favor of premature death. B shows the phenotype of these neurons with p53 mutation rescue, including morphology, suggesting a non-survival action for the p53 protein. Note that even in the wild-type, the absence of p53 has a dramatic effect on neuronal morphology.