Retromer sorting: a pathogenic pathway in late-onset Alzheimer disease.
Arch Neurol. 2008 Mar;65(3):323-8.
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Overall, this is an intriguing study. It lends further proof to the emerging concept that regulation of protein trafficking in neurons is an important mechanism in neurodegenerative disease processes. In line with this notion, a number of factors involved in regulation of neuronal protein transport such as sorting receptors (SORLA/LR11), sorting adaptors (GGA), or retromer components have all been implicated in processes related to Alzheimer disease in patients and animal models.
It is striking to note that a moderate decrease in expression of retromer components VPS26 and VPS35 in the retromer-deficient mouse model (50 percent reduction) has such profound consequences for APP processing as well as for functional integrity of the hippocampus. As such, these findings seem to indicate a central role for the retromer complex in neurodegenerative processes.
It will be interesting to see whether deficiency in retromer expression (as described for mouse and fly models herein) also coincides with abnormal trafficking of APP, of secretases, or of presumed retromer targets SORLA and sortilin—an observation that would ultimately provide a mechanistic model for the disturbances in neuroanatomy and behavior in retromer-deficient animal models reported here.
Small and colleagues (1) had previously shown that VPS26 and VPS35 are decreased in AD brains and that siRNA-mediated depletion of VPS26 and VPS35 produces an increase in Aβ levels in vitro. In this interesting paper, Muhammad and colleagues report that VPS26 haploinsufficiency increases levels of Aβ in both mouse and fly models. They also show that retromer deficiency produces memory deficits and synaptic dysfunction in VPS26+/- mice. Moreover, retromer deficiency results in neurodegeneration in a fly expressing human APP and BACE. A large number of proteins have been found to be altered in postmortem brain samples from AD subjects. However, the significance of such alterations needs to be tested in vivo, and this paper represents an excellent example. The finding that sAPPβ and Aβ levels are increased suggests that β-secretase activity is increased in VPS26+/- mice. He and colleagues (2) have previously shown that in vitro depletion of VPS26 results in accumulation of BACE in endosomes, most likely due to defective transport of BACE from endosomes to the trans-Golgi network. Our group has shown that depletion of the trafficking molecule GGA3 produces an increase in BACE and Aβ levels owing to impaired lysosomal degradation of BACE (3,4). Furthermore, we have found that GGA3 levels are decreased in AD brains and inversely correlate with BACE levels (3). Several groups have shown that BACE protein levels and activity are increased in AD brains. Many mechanisms have been proposed to explain such increases. Thus, it would be interesting to test whether retromer deficiency alters BACE protein levels or affects β-secretase activity by altering its subcellular localization in vivo.