This work from Dudley Strickland's lab describes a new protein related to the LDL receptor family, termed LRAD3. This protein shares structural similarities to other members of the family, including domains for the internalization and sorting of (as yet) unidentified ligands. It also shares another interesting characteristic: It interacts with APP and affects its processing. Interactions with APP have already been demonstrated for several members of the LDL receptor family, including LRP1 (Kounnas et al., 1995; Waldron et al., 2008), ApoER2 (Fuentealba et al., 2007), and sorLA (Andersen et al., 2005; Spoelgen et al., 2006). Both families share common adaptor proteins (Fe65, X11, Dab1), and the structure of LRAD3 suggests that it may interact with some of these adaptor proteins as well. These observations are even more interesting, since the functions of...  Read more

This work from Dudley Strickland's lab describes a new protein related to the LDL receptor family, termed LRAD3. This protein shares structural similarities to other members of the family, including domains for the internalization and sorting of (as yet) unidentified ligands. It also shares another interesting characteristic: It interacts with APP and affects its processing. Interactions with APP have already been demonstrated for several members of the LDL receptor family, including LRP1 (Kounnas et al., 1995; Waldron et al., 2008), ApoER2 (Fuentealba et al., 2007), and sorLA (Andersen et al., 2005; Spoelgen et al., 2006). Both families share common adaptor proteins (Fe65, X11, Dab1), and the structure of LRAD3 suggests that it may interact with some of these adaptor proteins as well. These observations are even more interesting, since the functions of members of the APP and LDL receptor families may be related: Evidence shows that both families affect neuron migration during development, and both affect synapse structure in mature neurons.

This study provides further data demonstrating that our understanding of APP trafficking, metabolism, and function will require our understanding of members of the LDL receptor family, including LRAD3.

View all comments by G. William Rebeck

This work looks very solid and very interesting. We seem to have moved from the “secretase generation” to the “sortase generation,” what with LRP, vps35, SORL1, and SORCS1 all playing key roles in sorting APP and its C-terminal fragments in and out of Aβ-generating and Aβ-lytic compartments.

This is all well and good, but what we really need is a clinical success. We now know how to lower Aβ with drugs or vaccines, but we don’t yet know whether pre-symptomatic Aβ lowering will prevent dementia, nor do we know how early is early enough. Based on the Dominantly Inherited Alzheimer Network (DIAN) and published data, and the desire not to start too soon the first time, it looks to me as if we have to begin treating people with presenilin-1 mutations at least 20 years before age at onset. Maybe 25 years is early enough.

While waiting for those DIAN data, we need to focus on potential prophylactic interventions with more impeccable safety profiles than we might accept for therapeutics, because we face the prospect of treating...  Read more

This work looks very solid and very interesting. We seem to have moved from the “secretase generation” to the “sortase generation,” what with LRP, vps35, SORL1, and SORCS1 all playing key roles in sorting APP and its C-terminal fragments in and out of Aβ-generating and Aβ-lytic compartments.

This is all well and good, but what we really need is a clinical success. We now know how to lower Aβ with drugs or vaccines, but we don’t yet know whether pre-symptomatic Aβ lowering will prevent dementia, nor do we know how early is early enough. Based on the Dominantly Inherited Alzheimer Network (DIAN) and published data, and the desire not to start too soon the first time, it looks to me as if we have to begin treating people with presenilin-1 mutations at least 20 years before age at onset. Maybe 25 years is early enough.

While waiting for those DIAN data, we need to focus on potential prophylactic interventions with more impeccable safety profiles than we might accept for therapeutics, because we face the prospect of treating clinically normal, pre-symptomatic subjects for at least as long (i.e., 25 years) in the first approximation.

The cell biology of the new Strickland paper provides yet another potentially druggable strategy for Aβ lowering. The data are clear and compelling, but it would be a whole lot easier to whip up enthusiasm if we were getting some runs on the board with Aβ-lowering interventions in the clinic.

View all comments by Samuel Gandy

There is no question that the complex processing of amyloid-β precursor protein (APP), via at least two intensely studied pathways (α- and β-secretase cleavage) that are relevant to Alzheimer’s disease (AD), occurs during APP’s still insufficiently understood journey within neurons along the secretory, endocytic, and degradative routes. It follows that the mechanisms and proteins that regulate intracellular trafficking of APP are most likely to affect processing of the precursor by altering its targeting into, or out of, different compartments. Based on what is currently known, proteins that regulate APP processing are potential targets for drugs against AD. Ranganathan et al. now add another protein to the plethora of those that bind (directly or indirectly) APP and regulate production of amyloid-β (Aβ). What is important is that the newly identified protein, LRAD3, an LDL receptor family member, participates in endocytic processes. Based on this role, and on the fact that LRAD3 affects APP proteolytic cleavage—an event that mostly occurs along APP’s endocytic route—the authors...  Read more

There is no question that the complex processing of amyloid-β precursor protein (APP), via at least two intensely studied pathways (α- and β-secretase cleavage) that are relevant to Alzheimer’s disease (AD), occurs during APP’s still insufficiently understood journey within neurons along the secretory, endocytic, and degradative routes. It follows that the mechanisms and proteins that regulate intracellular trafficking of APP are most likely to affect processing of the precursor by altering its targeting into, or out of, different compartments. Based on what is currently known, proteins that regulate APP processing are potential targets for drugs against AD. Ranganathan et al. now add another protein to the plethora of those that bind (directly or indirectly) APP and regulate production of amyloid-β (Aβ). What is important is that the newly identified protein, LRAD3, an LDL receptor family member, participates in endocytic processes. Based on this role, and on the fact that LRAD3 affects APP proteolytic cleavage—an event that mostly occurs along APP’s endocytic route—the authors propose that LRAD3 modulates APP trafficking, and in this way, also modulates APP processing. The study actually does not directly address the issue of APP trafficking, and it still remains to be demonstrated that the proposed mechanism indeed constitutes the basis for the increased amyloidogenic cleavage of APP, and generation of Aβ by overexpressed LRAD3. It is also possible—although less likely—that increased expression of LRAD3 disrupts the interaction of APP with other endogenous APP binding proteins that themselves could play roles in APP processing.

There is no doubt that this study is relevant to AD. The increased levels of secreted Aβ, detected in this study in the conditioned medium upon overexpression of LRAD3 in cultured cells, point to a potential source of the toxic extracellular Aβ in the AD brain. It would be also interesting to know if, under these conditions, the neurons also contain increased levels of Aβ. This is especially important considering the current debate on the role of intraneuronal Aβ in the pathogenic process of AD, as discussed in the ARF Webinar: Intraneuronal Aβ: Was It APP All Along?. Finally, we would like to point to the possibility that, by modulating the metabolism of APP, and the generation of APP-derived polypeptides, LRAD3 could very well regulate the function of full-length APP and its fragments, whatever those functions are (1). One cannot disregard the possibility that dysregulated APP or its fragments (other than Aβ) (2), in addition to potential detrimental effects on neuronal physiology (3,4), might contribute to AD pathology. While Aβ is part of the mechanisms leading to AD, it certainly is not the only player (5,6).

References:
1. Zheng H, Koo EH. Biology and pathophysiology of the amyloid precursor protein. Mol Neurodegener. 2011;6(1):27. Abstract

2. Muresan V, Varvel NH, Lamb BT, Muresan Z. The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci. 2009 Mar 18;29(11):3565-78. Abstract

3. Giliberto L, Zhou D, Weldon R, Tamagno E, De Luca P, Tabaton M, D'Adamio L. Evidence that the Amyloid beta Precursor Protein-intracellular domain lowers the stress threshold of neurons and has a "regulated" transcriptional role. Mol Neurodegener. 2008;3:12. Abstract

4. Passer B, Pellegrini L, Russo C, Siegel RM, Lenardo MJ, Schettini G, Bachmann M, Tabaton M, D'Adamio L. Generation of an apoptotic intracellular peptide by gamma-secretase cleavage of Alzheimer's amyloid beta protein precursor. J Alzheimers Dis. 2000 Nov;2(3-4):289-301. Abstract

5. Herrup K. Reimagining Alzheimer's disease--an age-based hypothesis. J Neurosci. 2010 Dec 15;30(50):16755-62. Abstract

6. Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH. Amyloid-independent mechanisms in Alzheimer's disease pathogenesis. J Neurosci. 2010 Nov 10;30(45):14946-54. Abstract

View all comments by Zoia Muresan
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