1 August 2011. The family of low-density lipoprotein (LDL) receptors has captured the interest of Alzheimer’s researchers, because several of these transmembrane sorting proteins help cells crank out Aβ. In the July 27 Journal of Neuroscience, researchers led by Dudley Strickland at the University of Maryland, Baltimore, introduce a novel family member, christened low-density lipoprotein receptor class A domain containing 3 (LRAD3). Like many of its siblings, the new kid can interact with amyloid precursor protein (APP), and it increases Aβ levels in cultured cells. LRAD3 seems to bind different protein partners than its kin do, suggesting it could act through distinct signaling pathways. Although much work remains to be done to show that this protein plays a role in AD in vivo, the discovery could potentially open up new routes for modulating Aβ production.
Other members of the LDL receptor family, as well as other related sorting proteins, have been shown to take a hand in increasing or decreasing Aβ generation by moving APP into intracellular compartments, where it is either snipped to release Aβ or digested. For example, LDL receptor-related protein 1 (LRP1) helps pump up Aβ levels (see, e.g., Kounnas et al., 1995; Ulery et al., 2000; Pietrzik et al., 2002; Pietrzik et al., 2004; and Waldron et al., 2008), as does the apolipoprotein E receptor 2 (see Fuentealba et al., 2007). The sorting protein SorCS1, by contrast, reduces Aβ generation (see ARF related news story on Lane et al., 2010). “We seem to have moved from the ‘secretase generation’ to the ‘sortase generation,’” Sam Gandy at Mount Sinai Medical Center wrote to ARF (see full comment below).
To discover whether the LDL receptor family held hidden members, first author Sripriya Ranganathan screened a database of human expressed sequence tags and turned up LRAD3. LRAD3’s sequence shows several differences compared to other LDL receptor family members, suggesting the new protein may bind distinct extracellular ligands and/or intracellular partners. In support of this, LRAD3 failed to bind receptor-associated protein (RAP), a common ligand for the family, and did not interact with the intracellular adaptor protein Fe65, which binds LRP1 and helps it interact with APP. Fe65 is implicated in APP signaling (see ARF related news story).
Analysis of human RNA showed that LRAD3 is expressed in many tissues, including total brain extract. Staining of mouse brain sections clarified the picture, revealing the presence of LRAD3 in hippocampus and cortex, among other regions. In cell culture experiments, LRAD3 sat in the cell membrane and was able to bring ligands into the cell through endocytosis, although more slowly than LRP1 does. Co-immunoprecipitations showed that LRAD3 interacts with APP, although it is not known if the interaction is direct or if it occurs through an adaptor protein. In cell culture, LRAD3 alters APP handling in a similar way as LRP1 does, pushing processing toward the amyloidogenic pathway.
As might be expected from a new find, numerous questions remain to be answered. Strickland said they are working on developing an LRAD3 knockout mouse, which they plan to cross with an AD mouse model to look for in-vivo effects on AD pathology. The authors are also actively searching for ligands and adaptor proteins that bind LRAD3, and hope to elucidate those pathways soon.
“This is solid work,” said Guojun Bu at the Mayo Clinic in Jacksonville, Florida. He suggested that one intriguing direction for future studies will be to look for mutations in LRAD3, or changes in its gene expression that associate with human AD. If these exist, it would strengthen the case for LRAD3 playing a significant role in disease pathology. Strickland said this is something he hopes to do.
Joachim Herz at UT Southwestern, Dallas, Texas, is most interested in what connection LRAD3 might have with ApoE, the most important risk factor for sporadic AD. “What makes the LDL receptor gene family special is that they can physically interact with ApoE,” he noted, and, therefore, these receptors forge a direct link between ApoE and amyloid generation. Herz believes the key question is whether isoforms of ApoE can modulate LRAD3 activity. If they can, it would suggest LRAD3 might play a dynamic role in AD pathology. If LRAD3 activity is not easily modified, on the other hand, the receptor could be just a housekeeping gene that regulates baseline trafficking of APP, Herz suggested. Strickland told ARF he is planning to investigate this question in collaboration with ApoE expert Karl Wiesgraber at the Gladstone Institute for Neurodegenerative Diseases, San Francisco, California.—Madolyn Bowman Rogers.
Ranganathan S, Noyes NC, Migliorini M, Winkles JA, Battey FD, Hyman BT, Smith E, Yepes M, Mikhailenko I, Strickland DK. LRAD3, a novel low-density lipoprotein receptor family member that modulates amyloid precursor protein trafficking. J Neurosci. 2011 Jul 27;31(30):10836-46. Abstract