Rohe M, Carlo AS, Breyhan H, Sporbert A, Militz D, Schmidt V, Wozny C, Harmeier A, Erdmann B, Bales KR, Wolf S, Kempermann G, Paul SM, Schmitz D, Bayer TA, Willnow TE, Andersen OM. Sortilin-related receptor with A-type repeats (SORLA) affects the amyloid precursor protein-dependent stimulation of ERK signaling and adult neurogenesis. J Biol Chem. 2008 May 23;283(21):14826-34. PubMed.
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UCLA/VA
This new data on curcumin stimulated neurogenesis look pretty good and the dosing at 500nM to get the effect in vitro and via stimulation of MAPK is credible and consistent with other literature. Their in vivo results are the most important demonstration of possible utility. The dosing is higher than what people achieve with current supplements and the blood and brain levels represent estimates. They are at the high end, but the authors get the neurogenesis effect without toxicity, suggesting that it may be realizable within a therapeutic window.
One caveat for the relevance to AD for this and for most of the other studies showing stimulation of hippocampal neurogenesis is that the effects shown are usually in the dentate gyrus rather than in more AD vulnerable regions like CA1, entorhinal cortex and other areas showing neuron loss. That said, the increases in areas with normal neurogenesis, in the DG and in the cortical subventricular zone, suggests an effect might extend to other areas and might redistribute to areas of neuron loss in the presence of regional pathology.
View all comments by Gregory ColeUniversità di Napoli Federico II
This interesting paper of Thomas Willnow and colleagues confirms that SORLA/LR11 has a significant role in the regulation of APP processing, thus giving further support to the hypothesis that reduced SORLA expression could be a risk factor for sporadic AD (Rogaeva et al., 2007).
In addition, the results suggest some other reflections. First, they confirm that, at least in mice, altered neuronal function and survival are not directly correlated with the amount of Aβ produced and with plaque burden. This is the umpteenth observation that draws our attention to this point, but we still don’t have a clear explanation for that. Second, the results contribute to the unsolved issue of APP functions. The observed molecular phenotypes are actually due to an increased processing of APP that leads to accumulation of secreted soluble APP. However, we should also take into account that increased processing of APP is also expected to affect AICD intracellular concentration. Thus, we cannot exclude that the observed phenotype could be due to altered AICD-dependent signaling. This possibility is also supported by the recent data of Quan-Hong Ma and colleagues (Quan-Hong Ma et al., 2008) indicating that TAG1-APP signaling modulates neurogenesis through AICD-Fe65. The problem is that the two papers observed an increased neurogenesis in two apparently opposite conditions, namely, increased processing of APP (with overproduction of APPs and Aβ) and absence of APP (no production of AICD), respectively. However, this is not the first time that increased production of Aβ and APPs is associated with low levels of AICD. The SORLA-/- background could be a good tool to address this point.
References:
Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
Ma QH, Futagawa T, Yang WL, Jiang XD, Zeng L, Takeda Y, Xu RX, Bagnard D, Schachner M, Furley AJ, Karagogeos D, Watanabe K, Dawe GS, Xiao ZC. A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol. 2008 Mar;10(3):283-94. PubMed.
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