Neurogenesis Gets a Jolt From Enhanced APP Processing, Curcumin

The birth of new neurons in the adult brain intimates a capacity for restoration even in the face of aging and neurodegeneration. Two papers published in the March 24 issue of the Journal of Biological Chemistry online highlight a pair of scenarios where neurogenesis could come into play in Alzheimer disease. One study, from Thomas Willnow and colleagues at the Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany, indicates that lack of the trafficking receptor SORLA causes overproduction of soluble APP products and increased neurogenesis. Both decreased SORLA and increased neurogenesis have been observed in AD brain, and the study provides a possible link between the two.

The second study, from Jaewon Lee and colleagues at Pusan National University in Korea, presents evidence that curcumin, a component of curry spice with anti-inflammatory, antioxidant and anti-amyloid activity, also enhances neurogenesis in the brain of adult mice. Though it is not clear if neurogenesis explains curcumin’s repertoire of actions, the results suggest another way in which the compound might benefit the brain.

In the SORLA story, previous work from Willnow and colleagues showed that SORLA, also an ApoE receptor and alternatively known as LR11, controls processing of the amyloid precursor protein (APP) by directing its travel through subcellular compartments (see ARF related news story). High levels of SORLA result in less APP cleavage, while the lower concentrations found in the brains of people with AD (Scherzer et al., 2004) or mild cognitive impairment (Sager et al., 2007) may promote amyloidogenic processing of APP. SORLA is particularly interesting because it is decreased in brains of people with sporadic AD, but not familial disease, suggesting the reduction may be a cause of pathology, not a result. Consistent with this idea, polymorphisms in the gene encoding SORLA (SORL1) have been associated with late-onset AD (see ARF related news story and AlzGene entry).

In the new study, authors Michael Rohe and Anne-Sophie Carlo used SORLA knockout mice (Andersen et al., 2005) to understand the physiological role of the protein and its effects on Aβ pathology in vivo. Their results coincide with previous studies in cells, suggesting that SORLA serves to keep the lid on amyloidogenic APP processing. SORLA knockout mice, they show, had lower levels of full-length APP and higher amounts of APP cleavage products in the hippocampus. When they crossed SORLA knockout mice with PDAPP mice expressing a mutated form of human APP, the offspring showed increases in the levels of soluble APP products and Aβ40 peptide in the hippocampus and a threefold in increase in plaque burden. These results suggest that the diminished SORLA levels seen in sporadic AD could encourage senile plaque formation. Nonetheless, the investigators did not see changes in synaptic transmission in the hippocampus of SORLA-lacking mice compared to the impairments already seen in the PDAPP parental mice.

Soluble APP fragments have been reported to stimulate MAP kinase pathways (Greenberg et al., 1994), which are important in neurogenesis. When the investigators looked in the SORLA-deficient mice, they found that the observed 50 percent increase in sAPP was accompanied by activation of the MAP kinase ERK. BrdU labeling to detect dividing cells revealed a threefold increase in the number of proliferating cells in the hippocampus shortly after labeling, and a twofold increase in the number of surviving BrdU-labeled cells four weeks later. This effect on neurogenesis was likely due to APP processing since labeled cells were not found in SORLA knockout mice that also lacked APP. The investigators conclude, “Our data document a role for SORLA not only in control of plaque burden, but also in APP-dependent neuronal signaling, and suggest a molecular explanation for increased neurogenesis observed in some AD patients.”

The second paper, a study of the effects of curcumin on neurogenesis, follows on two other reports of positive effects of the compound on neurogenesis in chronically stressed rats (Xu et al., 2007) and in normal mice (Kang et al., 2006). Curcumin, a component of turmeric, the yellow spice that colors curries, has been shown to reduce plaque accumulation and improve cognitive function in mouse models, and inhibit Aβ aggregation (reviewed in Cole et al., 2007; see also ARF related news story and ARF news story). Based on these results, pilot clinical trials are in progress (see ARF related news story), and the results from one preliminary study in China were recently published (Baum et al., 2008).

The new work shows that curcumin at low concentrations increases the proliferation of neural progenitor cells in vitro, in association with its ability to activate the map kinases ERK and p38. In vivo, administration of curcumin to adult mice resulted in increased numbers of newly born cells both in the dentate gyrus of the hippocampus and in the subventricular region of the cerebral cortex of adult mice, centers of neurogenesis. Four weeks later, all the newborn cells had turned into neurons. The effect of curcumin on neurogenesis was similar to the impact of exercise and environmental enrichment. The stimulation of neurogenesis represents “another potential useful effect” of curcumin, says Greg Cole of the University of California at Los Angeles, who was not involved with this study but has worked on curcumin extensively. However, he said, “It is hard to know the significance yet.”—Pat McCaffrey

Comments

  1. 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 Cole

  2. 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.

    View all comments by Tommaso Russo

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References

News Citations

  1. Sorting Out SorLA—What Role in APP Processing, AD?
  2. SORLA Soars—Large Study Links Gene to Late-onset AD
  3. Curry Ingredient Spices Things Up by Blocking Aβ Aggregation
  4. Potential Therapies—Small Molecule Boosts for Immune Response, Neurogenesis
  5. Oakland: Food for Thought at American Aging Association Annual Meeting

Paper Citations

  1. Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004 Aug;61(8):1200-5. PubMed.
  2. Sager KL, Wuu J, Leurgans SE, Rees HD, Gearing M, Mufson EJ, Levey AI, Lah JJ. Neuronal LR11/sorLA expression is reduced in mild cognitive impairment. Ann Neurol. 2007 Dec;62(6):640-7. PubMed.
  3. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. PubMed.
  4. Greenberg SM, Koo EH, Selkoe DJ, Qiu WQ, Kosik KS. Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7104-8. PubMed.
  5. Xu Y, Ku B, Cui L, Li X, Barish PA, Foster TC, Ogle WO. Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats. Brain Res. 2007 Aug 8;1162:9-18. PubMed.
  6. Kang SK, Cha SH, Jeon HG. Curcumin-induced histone hypoacetylation enhances caspase-3-dependent glioma cell death and neurogenesis of neural progenitor cells. Stem Cells Dev. 2006 Apr;15(2):165-74. PubMed.
  7. Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Adv Exp Med Biol. 2007;595:197-212. PubMed.
  8. Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, Lam L, Leung V, Hui E, Ng C, Woo J, Chiu HF, Goggins WB, Zee BC, Cheng KF, Fong CY, Wong A, Mok H, Chow MS, Ho PC, Ip SP, Ho CS, Yu XW, Lai CY, Chan MH, Szeto S, Chan IH, Mok V. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol. 2008 Feb;28(1):110-3. PubMed.

External Citations

  1. AlzGene entry

Further Reading

Papers

  1. Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci. 2008 Jun;65(11):1631-52. PubMed.

Primary Papers

  1. 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.
  2. Kim SJ, Son TG, Park HR, Park M, Kim MS, Kim HS, Chung HY, Mattson MP, Lee J. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem. 2008 May 23;283(21):14497-505. PubMed.

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