It is intriguing that SorCS1 (see AlzGene) has gender differences in functional effects on Aβ production as well as in the Liang et al., 2009, linkage study. Of course, it makes sense in that it ties into the overall story that genetic differences that increase Aβ production increase risk. It would be nice to see particular genetic variants influencing Aβ production rather than the manipulations of the whole protein level, but that is where we are with SorLA and now with SorCS1.

The issues with both SorLa and now SorCS1, and in fact with nearly every genetic risk factor beyond ApoE, are that most seem tied to Aβ accumulation, the effect size of polymorphisms is low, and specific functional mutations or alleles are not very clear. Modest effect sizes for SNPs in these genes don't mean you won't have potentially important targets for lowering Aβ. However, therapeutic relevance may be limited by issues of specificity with the more...  Read more

It is intriguing that SorCS1 (see AlzGene) has gender differences in functional effects on Aβ production as well as in the Liang et al., 2009, linkage study. Of course, it makes sense in that it ties into the overall story that genetic differences that increase Aβ production increase risk. It would be nice to see particular genetic variants influencing Aβ production rather than the manipulations of the whole protein level, but that is where we are with SorLA and now with SorCS1.

The issues with both SorLa and now SorCS1, and in fact with nearly every genetic risk factor beyond ApoE, are that most seem tied to Aβ accumulation, the effect size of polymorphisms is low, and specific functional mutations or alleles are not very clear. Modest effect sizes for SNPs in these genes don't mean you won't have potentially important targets for lowering Aβ. However, therapeutic relevance may be limited by issues of specificity with the more basic downstream sorting machinery for proteins like SorCS1. The closer you get to the secretases, the better chance you have for specificity and good therapeutic targets. So I would place SorCS1 in the category of potentially relevant.

That said, over a lifetime, small differences in sorting rates from variants that modestly impact Aβ production rates may have dramatic long term impact. You can make the analogy to compound interest rates, where a quarter point or half point difference in interest seems trivial and doesn't make a significant difference in an 18 month investment portfolio (or clinical trial) but adds up over the decades to really make a difference. My view is that SorLA and SorCS1 and other candidate late-onset AD genes tied to Aβ accumulation are best thought of in the context of prevention. Can we find safe ways to influence them that shift the long-term Aβ balance sheet in our favor?

View all comments by Gregory Cole

I love reading these stories. It makes me extremely knowledgeable.

View all comments by Dharmendra Zala

Faulty transport along the endocytic route in neurons is emerging as an important molecular mechanism underlying enhanced APP processing in AD. One pathway elucidated in some detail entails SorLA (aka SORL1 or LR11), a neuronal sorting protein for APP, and retromer, a trafficking adaptor complex that sorts cargo from endosomes to the Golgi. Previously, a number of studies provided independent experimental evidence implicating impaired expression of SORLA and retromer in aggravated APP processing and amyloid-β peptide production in both animal models and in patients. From these studies, a model was proposed whereby SorLA re-routes internalized APP molecules from early endosomes back to the Golgi, bypassing delivery of the precursor protein to late endosomes where β-secretases reside. Because the cytoplasmic tail of SorLA includes a proposed binding motif for retromer, this adaptor complex was suggested to direct retrograde trafficking of SorLA/APP complexes from endosomal to Golgi compartments.

Now, three studies have further substantiated this model by providing important...  Read more

Faulty transport along the endocytic route in neurons is emerging as an important molecular mechanism underlying enhanced APP processing in AD. One pathway elucidated in some detail entails SorLA (aka SORL1 or LR11), a neuronal sorting protein for APP, and retromer, a trafficking adaptor complex that sorts cargo from endosomes to the Golgi. Previously, a number of studies provided independent experimental evidence implicating impaired expression of SORLA and retromer in aggravated APP processing and amyloid-β peptide production in both animal models and in patients. From these studies, a model was proposed whereby SorLA re-routes internalized APP molecules from early endosomes back to the Golgi, bypassing delivery of the precursor protein to late endosomes where β-secretases reside. Because the cytoplasmic tail of SorLA includes a proposed binding motif for retromer, this adaptor complex was suggested to direct retrograde trafficking of SorLA/APP complexes from endosomal to Golgi compartments.

Now, three studies have further substantiated this model by providing important additional evidence to support a role for retromer in SorLA-dependent sorting of APP. Thus, work by Fjorback et al. finally confirmed a hexapeptide motif (FANSHY) in the cytoplasmic tail of SorLA as a binding site for Vps26, a subunit of the retromer complex. A SorLA mutant lacking the FANSHY motif retained APP-binding activity but failed to properly directe APP to the Golgi, resulting in increased amyloidogenic processing. In a study from the lab of Scott Small, immunocytochemical investigations were applied to elucidate, in detail, the trafficking routes taken by retromer complex in primary neurons. Gratifyingly, these studies confirmed the necessity of retromer to guide long-range transport of APP along the axonal path. Knockdown of Vps35, another subunit of the retromer complex, resulted in accumulation of APP in endosomal compartments, in increased colocalization with BACE, and in elevated levels of Aβ.

Finally, a new study published by Matthew Seaman and Lindsay Farrer and their colleagues identified genetic association of AD with several vesicular trafficking proteins. Amongst these, SNX3 and RAB7A were further shown to represent novel regulatory components to control membrane association of retromer. Taken together, these recent studies provide exciting new data that consolidate abnormal intracellular trafficking of APP by SORLA as an underlying cause of amyloidogenic processing. It will be exciting to learn more about the molecular mechanisms whereby sequence variations affect expression or activity of pathway components in individuals at risk of sporadic AD.

View all comments by Thomas Willnow

The three recent papers discussed here (1-3) shed new light on the role of retromer in intracellular trafficking, and on the proteolytic processing of the amyloid-β precursor protein (APP) and the consequences of its abnormal function for the pathogenic process in Alzheimer’s disease (AD). Retromer is an adaptor protein with roles in regulating the trafficking between endosomes and the Golgi apparatus, most likely retrograde trafficking. Other adaptor proteins that regulate various steps along the complex route of APP transport to and from the cell surface, and between intracellular compartments, could similarly impact the processing of APP. This is the case with Fe65 (4), Mint1/X11 (5), JIP-1 (6,7), and DISC1 (8), to name just a few of them. Thus, it becomes clear that the aberrant processing of APP that leads to increased generation and/or decreased clearance of Aβ is likely caused by diversion of APP from its normal transport route. Accordingly, searching for proteins that perturb trafficking of APP using large-scale screening assays is now more important than ever. Using dual...  Read more

The three recent papers discussed here (1-3) shed new light on the role of retromer in intracellular trafficking, and on the proteolytic processing of the amyloid-β precursor protein (APP) and the consequences of its abnormal function for the pathogenic process in Alzheimer’s disease (AD). Retromer is an adaptor protein with roles in regulating the trafficking between endosomes and the Golgi apparatus, most likely retrograde trafficking. Other adaptor proteins that regulate various steps along the complex route of APP transport to and from the cell surface, and between intracellular compartments, could similarly impact the processing of APP. This is the case with Fe65 (4), Mint1/X11 (5), JIP-1 (6,7), and DISC1 (8), to name just a few of them. Thus, it becomes clear that the aberrant processing of APP that leads to increased generation and/or decreased clearance of Aβ is likely caused by diversion of APP from its normal transport route. Accordingly, searching for proteins that perturb trafficking of APP using large-scale screening assays is now more important than ever. Using dual immunolocalization cytochemistry, we have previously found that, in neurons, Aβ accumulations within neurites strongly colocalize with BACE1 and Rab7 (9), a small GTPase that regulates late endocytic trafficking, including recruitment of retromer to endosomes. Interestingly, Vardarajan et al. (1) identified significant association of AD with SNPs in the Rab7A gene. However, we note that Rab7, while regulating late endosomal trafficking, is also required for the normal progression of autophagy (10), another trafficking pathway proposed to be dysregulated in AD. Since it is known that the retromer also regulates autophagocytosis (11), one wonders whether abnormal function of the retromer affects the generation of Aβ along the endocytic or autophagocytic pathway.

We would also like to draw attention to another issue covered by these interesting papers that is not fully settled—the site of action of the retromer. This has major implications for another unsolved problem—the intracellular site of production and accumulation of Aβ. Currently, it is accepted that the retromer plays a role in regulating the endosome-to-Golgi retrieval pathway. Much of this retrieval does take place in the cell body, as many previous studies have shown, and a significant fraction of cell surface APP is internalized, and Aβ is generated in endosomes in the neuronal soma (see, e.g., our studies [8,9]). However, Bhalla et al. (2) now show that the retromer may primarily function in axons and dendrites rather than in the soma, an interesting finding that needs to be confirmed in future studies. Since Aβ is also generated at the synapse (12), would abnormal retromer function facilitate generation and accumulation of Aβ at synapses?

Fjorback et al. (3) clarify the mechanism by which the retromer regulates the processing of APP, and show a direct interaction of the retromer with SorLA, a sorting receptor for APP, previously shown to be linked to AD. According to the proposed mechanism, the SorLA-retromer complex normally functions to retrieve APP via the endosome-to-Golgi pathway. This model nicely explains the increased generation of Aβ in an endosomal compartment when the SorLA-retromer complex does not properly function. Still, the precise site of action of SorLA, as well as the site of intracellular generation of Aβ, remain issues not fully understood (13). Certainly, there is still much to be learned from future studies about the relationship between trafficking and processing of APP, as well as about the relevance of abnormal intracellular transport of APP for AD (14).

References:
1. Vardarajan BN, Bruesegem SY, Harbour ME, George-Hyslop PS, Seaman MN, Farrer LA. Identification of Alzheimer disease-associated variants in genes that regulate retromer function. Neurobiol Aging. 2012 Sep;33(9):2231.e15-30. Abstract

2. Bhalla A, Vetanovetz CP, Morel E, Chamoun Z, Di Paolo G, Small SA. The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Neurobiol Dis. 2012 Jul;47(1):126-34. Abstract

3. Fjorback AW, Seaman M, Gustafsen C, Mehmedbasic A, Gokool S, Wu C, Militz D, Schmidt V, Madsen P, Nyengaard JR, Willnow TE, Christensen EI, Mobley WB, Nykjaer A, Andersen OM. Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing. J Neurosci. 2012 Jan 25;32(4):1467-80. Abstract

4. Ando K, Iijima KI, Elliott JI, Kirino Y, Suzuki T. Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid. J Biol Chem. 2001 Oct 26;276(43):40353-61. Abstract

5. Mueller HT, Borg JP, Margolis B, Turner RS. Modulation of amyloid precursor protein metabolism by X11alpha /Mint-1. A deletion analysis of protein-protein interaction domains. J Biol Chem. 2000 Dec 15;275(50):39302-6. Abstract

6. Muresan Z, Muresan V. Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1. J Cell Biol. 2005 Nov 21;171(4):615-25. Abstract

7. Taru H, Kirino Y, Suzuki T. Differential roles of JIP scaffold proteins in the modulation of amyloid precursor protein metabolism. J Biol Chem. 2002 Jul 26;277(30):27567-74. Abstract

8. Muresan, V. and Z. Muresan, DISC1 controls production of amyloid-β (Aβ) by regulating intracellular trafficking of the Aβ precursor protein (APP) along the secretory, endocytic, and degradative route. Annual Meeting of the Society for Neuroscience, Washington, D.C., November 12-16, 2011.

9. Muresan Z, Muresan V. Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells. Mol Cell Biol. 2006 Jul;26(13):4982-97. Abstract

10. Gutierrez MG, Munafó DB, Berón W, Colombo MI. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci. 2004 Jun 1;117(Pt 13):2687-97. Abstract

11. Dengjel J, Høyer-Hansen M, Nielsen MO, Eisenberg T, Harder LM, Schandorff S, Farkas T, Kirkegaard T, Becker AC, Schroeder S, Vanselow K, Lundberg E, Nielsen MM, Kristensen AR, Akimov V, Bunkenborg J, Madeo F, Jäättelä M, Andersen JS. Identification of autophagosome-associated proteins and regulators by quantitative proteomic analysis and genetic screens. Mol Cell Proteomics. 2012 Mar;11(3):M111.014035. Abstract

12. Gouras GK, Tampellini D, Takahashi RH, Capetillo-Zarate E. Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease. Acta Neuropathol. 2010 May;119(5):523-41. Abstract

13. Choy RW, Cheng Z, Schekman R. Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network. Proc Natl Acad Sci U S A. 2012 Jun 18. Abstract

14. Muresan V, Muresan Z. Is abnormal axonal transport a cause, a contributing factor or a consequence of the neuronal pathology in Alzheimer's disease? Future Neurol. 2009 Nov 1;4(6):761-773. Abstract

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