4 April 2008. 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.
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. Sorla affects APP-dependent stimulation of erk signaling and adult neurogenesis. J Biol Chem. 2008 Mar 24; [Epub ahead of print] Abstract
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 Mar 24; [Epub ahead of print] Abstract