14 Nov 2000

One of the most daunting tasks facing attendees of this gigantic neuroscience data exchange (dare I say "flea market"?) is identifying signals in the noise (speaking both scientifically and literally). One approach is to sit through slide sessions and hope that the organizers will have done your work for you, providing a series of talks that will be both illuminating and informative. And sometimes this works. But there seems little doubt that most scientific exchange occurs at the poster sessions, an endurance test for veterans and novices alike. But here again, it is still difficult to know whether or not a particular observation represents a fluke or an emerging theme. So one approach to signal detection is to see whether or not the same message crops up in different places. On this count, there is an interesting tale in the making and the central player is a rather enigmatic protein tongue-twistingly named the low-density lipoprotein receptor-related protein (LRP, for short). What exactly this receptor is doing is hard to say with certainty. But it keeps cropping up in interesting places and seems to be hanging out with all the big AD players, e.g., Aß, APP, A2M, and ApoE.

Several posters from different laboratories reported on various aspects of LRP activity. For example, a group from San Diego (Abstract 858.11) found that LRP may be critical for clearing Aß in cultured cells. This apparently occurs by way of a complex formed between Aß and A2M. Another group from Boston (Abstract 858.13) has previously shown that LRP can bind and internalize the KPI form of APP, perhaps leading to Aß production as a result. They provided further evidence at this meeting that LRP can bind and internalize both APP and A2M using radiolabeled ligands. Yet another group from California (Abstract 858.14), which previously found that TGFß2 can deliver Aß to hippocampal neurons (TGFß1 apparently delivers Aß to microglia), found that the uptake into neurons (but into microglia) was blocked by RAP, a protein that inhibits binding of LRP ligands. The evidence is a bit more indirect, because RAP can bind to other members of the LDL receptor family, but it is consistent with the possibility that this interaction is also mediated by LRP. Other evidence suggests that this receptor may be playing roles in intracellular signaling. For example, calcium increases in cells exposed to ApoE or peptides derived from the receptor binding domain of ApoE can be blocked by RAP (Abstract 665.7) and A2M also causes calcium signaling through a mechanism that implicates both LRP and the NMDA receptor (Abstract 859.13). All in all, the mounting evidence points to LRP as doing something (maybe several things) but with so many potential partners and cellular effects, it could be a while before anyone is able to decipher the precise contribution it may make to AD pathology. The number of talented laboratories joining the search, however, provides hope that the answers will be coming soon.—Keith Crutcher