The sortilin-related receptor protein SORLA (aka SORL1) controls the trafficking and processing of the amyloid precursor protein (APP), and thus serves as a key regulator of amyloid-β (Aβ) production in the brain. But what regulates SORLA? A new report from Thomas Willnow of the Max Delbruck Center for Molecular Medicine, Berlin, Germany, and Anders Nykjaer, Aarhus University, Denmark, provides an intriguing answer to this question. In work published in the December 9 Journal of Neuroscience, Willnow, Nykjaer and colleagues show that brain-derived neurotrophic factor (BDNF) induces SORLA expression in mouse neurons in vitro and in vivo, which leads to a reduction in APP processing to Aβ. Both BDNF and SORLA are lacking in the brain in Alzheimer disease, and the study links the two, raising the possibility that some of the protective effects reported for BDNF in AD might stem from diminished Aβ production.
Willnow and Nykjaer had previously discovered that SORLA regulates the travels and processing of the amyloid precursor protein (APP), steering it away from cell compartments that favor amyloidogenic processing and thus reducing Aβ production (Andersen et al., 2005). Consistent with this role, knocking out SORLA worsens pathology in an AD mouse model (see ARF related news story on Dodson et al., 2008). Human studies implicated SORLA in AD. Expression of the receptor is reduced in brain tissue from AD patients (Scherzer et al., 2004; Dodson et al., 2006), and SORLA gene variants are associated with the risk of late-onset AD (see AlzGene entry for SORL1).
To explore possible regulators of SORLA, first author Michael Rohe took a screening approach, testing nine different trophic factors for their ability to elevate SORLA mRNA in newborn mouse primary cortical neurons in culture. The best inducer by far was BDNF, which caused a seven- to 10-fold elevation of SORLA mRNA and a 60 percent increase in protein levels within 48 hours of treatment. In vivo, too, BDNF appeared to be a major regulator of SORLA levels. Brain extracts from newborn BDNF knockout mice contained 40 percent less SORLA protein than did their normal littermates. Also, SORLA levels were down in a mouse model of Huntington disease, where loss of BDNF is part of the phenotype.
Given that SORLA restrains the amyloidogenic processing of APP, the researchers asked whether BDNF had any effect on Aβ production. They found that adding the growth factor to primary neurons slashed Aβ40 production by 40 percent. This depended on SORLA induction, as BDNF had no impact on neurons from SORLA knockout mice, despite the normal activation of the BDNF receptor and downstream signaling pathways. BDNF increased SORLA expression and reduced Aβ40 and 42 production in neurons from PDAPP mice, an AD model that overexpresses a mutant human APP gene. In vivo, intracranial injection of the factor into the hippocampi of mice caused a 40 percent drop in Aβ40 levels. Consistent with the in vitro work, no change in Aβ production was seen under the same treatment regimen in SORLA-deficient mice.
Finally, Willnow and colleagues looked at the signaling pathways involved in SORLA induction by BDNF. Processing of SORLA by γ-secretase has been shown to downregulate SORLA expression, but the German scientists found that treating cells with γ-secretase inhibitors did not interfere with the effects of BDNF. On the other hand, inhibiting the MEK/ERK pathway could prevent SORLA induction.
BDNF replacement has been proposed as a potential treatment for AD, based on its downregulation in AD brain and recent studies showing that chronic delivery of the factor either by lentiviral expression (see ARF related news story on Nagahara et al., 2009) or via stem cells (see ARF related news story on Blurton-Jones et al., 2009) improves synaptic density and cognition in two mouse models of AD. However, in neither study was there any reduction of plaque load in response to treatment, and the authors attribute the effects of BDNF to its better-known trophic actions.
How to reconcile the disparate results? The studies are difficult to compare with the new study, Willnow wrote in an e-mail to ARF, because models, treatment regimens, and endpoints measured were quite different. “In our work, we aimed at testing the acute effects of high doses of BDNF application in the hippocampus and in primary neurons on upregulation of SORLA gene expression and local Aβ formation. Therefore, we determined the amount of soluble Aβ formed acutely during seven days of BDNF infusion into the hippocampus. This experimental condition will not clarify whether chronic application of BDNF will also induce SORLA gene expression and reduce long-term Aβ formation and senile plaque deposition,” he noted.
“There is no doubt that BDNF has many pleiotropic effects on neuronal function and cognitive performance, some likely dependent, others independent of APP metabolism,” Willnow concluded. For SORLA aficionados, the work opens up a new set of interesting questions about whether and in what way their favorite protein may support the trophic actions of BDNF in neurons.—Pat McCaffrey