This new study showing association of SORL1 with late-onset Alzheimer disease (LOAD) provides further support for a role of this gene in AD, confirming earlier studies by Lah, Small, Gandy, Masters, and others implicating SORL1 in AD pathogenesis.

The novelty of this study is the inclusion of genetic association of several SNPs in SORL1 with various samples of different ethnicities. The results for specific SNPs across samples are interesting but inconsistent, with various SNPs showing positive results in some samples and negative data in others. This is often the case for many novel AD candidate genes when tested in multiple samples, either in a single study or across multiple studies.

The Alzgene.org database on Alzforum reveals no less than two dozen genes that exhibit statistically significant association with LOAD after meta-analyses of multiple samples. These can be found in the "Top Alzgene Results" box in the right margin of Alzgene. A full description of Alzgene and its findings can be found...  Read more

This new study showing association of SORL1 with late-onset Alzheimer disease (LOAD) provides further support for a role of this gene in AD, confirming earlier studies by Lah, Small, Gandy, Masters, and others implicating SORL1 in AD pathogenesis.

The novelty of this study is the inclusion of genetic association of several SNPs in SORL1 with various samples of different ethnicities. The results for specific SNPs across samples are interesting but inconsistent, with various SNPs showing positive results in some samples and negative data in others. This is often the case for many novel AD candidate genes when tested in multiple samples, either in a single study or across multiple studies.

The Alzgene.org database on Alzforum reveals no less than two dozen genes that exhibit statistically significant association with LOAD after meta-analyses of multiple samples. These can be found in the "Top Alzgene Results" box in the right margin of Alzgene. A full description of Alzgene and its findings can be found in Bertram et al., 2007 in this month's issue.

By statistical analyses on Alzgene prior to this paper, SORL1 would be roughly the twenty-fifth gene to show statistically significant association with LOAD after testing in multiple independent samples. To the authors' credit, a sufficient number of independent samples were tested in this new SORL1 paper to already lend itself to meta-analysis on Alzgene. According to Lars Bertram, these findings are now being added to the site and are summarized here. The bottom line is that several of the meta-analyses for the SORL1 SNPs tested are significant. However, the effect on risk is very modest—the strongest allelic odds ratio for SORL1 is only 1.21. This means that the strongest effect of any SNP in SORL1 in the new study would increase risk for AD by 21 percent. In contrast, one copy of ApoE4 increases risk by about 300 percent.

The top hits on the Alzgene site are ranked by strength of their effect on risk for AD. As expected, ApoE4 is number one. Based on the data in the new study by St George-Hyslop and colleagues, SORL1 would not make the top 10 list, but rank in at number 12 out of 25. So while SORL1 can be added to the list, its small effects on risk based on the multiple case-control samples tested, as well as the less impressive results across the family-based samples tested, would suggest that SORL1 will turn out to be a minor genetic risk factor for AD.

Additional replication testing will be needed to see if the effects on risk hold up over time. As with all AD gene candidates proposed beyond the established four AD genes (APP, PSEN1, PSEN2, ApoE), the true validity of SORL1 as a novel AD gene will need to await the identification of validated pathogenic mutations or variants.

View all comments by Rudy Tanzi

This work is welcome news from an excellent group of investigators. They will surely allow me to play devil’s advocate and caution two things. First, however enticing the cell biology might be, at this point it is a distraction. The question at hand is a genetic question, and to answer the genetics per se, the cell biology data is irrelevant. Unfortunately, journal editors often demand cell biology in genetics papers, even if it’s just an initial set of experiments.

Second, while many sample series were used, there is not an exact replication of the haplotypic association between the sample series, making these "replications," in my view, suspect. In this, the work resembles our own work (Li et al., 2006 and Grupe et al., 2006 on other risk genes). In these cases, too, we obtained multiple, but not entirely convincing replications.

Late-onset Alzheimer genetics is proving to be a very difficult problem. I personally doubt whether this is the new ApoE, but genuine attempts at...  Read more

This work is welcome news from an excellent group of investigators. They will surely allow me to play devil’s advocate and caution two things. First, however enticing the cell biology might be, at this point it is a distraction. The question at hand is a genetic question, and to answer the genetics per se, the cell biology data is irrelevant. Unfortunately, journal editors often demand cell biology in genetics papers, even if it’s just an initial set of experiments.

Second, while many sample series were used, there is not an exact replication of the haplotypic association between the sample series, making these "replications," in my view, suspect. In this, the work resembles our own work (Li et al., 2006 and Grupe et al., 2006 on other risk genes). In these cases, too, we obtained multiple, but not entirely convincing replications.

Late-onset Alzheimer genetics is proving to be a very difficult problem. I personally doubt whether this is the new ApoE, but genuine attempts at replication will sort that out reasonably quickly.

View all comments by John Hardy

Update: With regard to my earlier comment on the SORL1-AD genetic association study by Rogaeva et al, I initially commented that on the Alzgene list of "Top Alzgene Results", SORL1 ranked 12th out of 25 genes. (Ranking is based on effects of SNPs in the gene on risk for AD, with APOE at number 1).

Lars Bertram has now revised that ranking on the most updated "Top Alzgene Results" list:

SORL1 ranks 18th out of 27 genes listed on "Top Alzgene Results" that have statistically significant effects on AD risk following meta-analyses.

View all comments by Rudy Tanzi

This study by Böhm et al. is the first to show that the mosaic receptor SorLA/LR11 is a substrate for the γ-secretase complex and undergoes intramembraneous cleavage. The authors convincingly demonstrate that the SorLA carboxy-terminal fragment (SorLA-CTF) is cleaved by γ-secretase, releasing a SorLA β peptide and the SorLA intracellular domain (SorICD). Taken together with previously reported data on metalloprotease-mediated ectodomain shedding of SorLA (Hampe et al., 2000), this processing is reminiscent of the processing of other transmembrane proteins such as Notch and the amyloid precursor protein (APP).

In the case of Notch, the intracellular domain translocates to the nucleus and can regulate transcription. In an analogy to this signaling pathway, the authors of this study provide evidence suggesting that SorICD tagged with EGFP also localizes to the nucleus. However, they observed only a fairly weak transcriptional activation in a luciferase reporter assay. Addressing the typically short lifetime of ICDs produced by γ-secretase, the authors provide indirect evidence...  Read more

This study by Böhm et al. is the first to show that the mosaic receptor SorLA/LR11 is a substrate for the γ-secretase complex and undergoes intramembraneous cleavage. The authors convincingly demonstrate that the SorLA carboxy-terminal fragment (SorLA-CTF) is cleaved by γ-secretase, releasing a SorLA β peptide and the SorLA intracellular domain (SorICD). Taken together with previously reported data on metalloprotease-mediated ectodomain shedding of SorLA (Hampe et al., 2000), this processing is reminiscent of the processing of other transmembrane proteins such as Notch and the amyloid precursor protein (APP).

In the case of Notch, the intracellular domain translocates to the nucleus and can regulate transcription. In an analogy to this signaling pathway, the authors of this study provide evidence suggesting that SorICD tagged with EGFP also localizes to the nucleus. However, they observed only a fairly weak transcriptional activation in a luciferase reporter assay. Addressing the typically short lifetime of ICDs produced by γ-secretase, the authors provide indirect evidence that insulin-degrading enzyme might be responsible for the degradation of SorICD.

SorLA has recently been linked to Alzheimer disease (AD) in several ways: It is normally highly expressed in the brain, but reduced in AD brains (Scherzer et al., 2004); it has been shown to interact with APP and to regulate amyloid-β peptide (Aβ) levels (Andersen et al., 2005; Offe et al. 2006); and it was reported to interact with the β-secretase BACE (Spoelgen et al., 2006). The present paper extends the links between SorLA and AD to include an interaction with γ-secretase. SorLA thus interacts with all of the proteins immediately involved in Aβ generation and may emerge as an important player in the regulation of Aβ production and the progression of AD.

References:
Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC. Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci. 2000 Dec;113 Pt 24:4475-85. Abstract

Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004 Aug;61(8):1200-5. Abstract

Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. Epub 2005 Sep 7. Abstract

Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ. The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci. 2006 Feb 1;26(5):1596-603. Abstract

Spoelgen R, von Arnim CA, Thomas AV, Peltan ID, Koker M, Deng A, Irizarry MC, Andersen OM, Willnow TE, Hyman BT. Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci. 2006 Jan 11;26(2):418-28. Abstract

View all comments by James J. Lah
View all comments by Katrin Offe

SorLA—a new substrate for γ-secretase
Sorting protein-related receptor (SorLA) is a neuronal transmembrane protein that received considerable attention as a possible new factor involved in regulation of APP processing. Initially identified as a gene down-regulated in the brains of patients suffering from Alzheimer’s disease (1), detailed cell biological studies by Andersen et al. (2,3) and Offe and coworkers (4) demonstrated that SorLA directly interacts with the amyloid precursor protein (APP) and that it affects intracellular transport and processing of the precursor to the Aβ peptide. In general, increased expression of SorLA in neurons coincides with a reduction in Aβ production while inactivation of the gene in a knockout mouse model increases Aβ formation, suggesting a possible role for this receptor as inhibitor of APP processing and senile plaque formation. A mechanistic model of how SorLA may inhibit amyloidogenic peptide formation was provided by Spoelgen et al., who uncovered a close interaction of SorLA with the β-site APP cleaving enzyme (BACE) inhibiting...  Read more

SorLA—a new substrate for γ-secretase
Sorting protein-related receptor (SorLA) is a neuronal transmembrane protein that received considerable attention as a possible new factor involved in regulation of APP processing. Initially identified as a gene down-regulated in the brains of patients suffering from Alzheimer’s disease (1), detailed cell biological studies by Andersen et al. (2,3) and Offe and coworkers (4) demonstrated that SorLA directly interacts with the amyloid precursor protein (APP) and that it affects intracellular transport and processing of the precursor to the Aβ peptide. In general, increased expression of SorLA in neurons coincides with a reduction in Aβ production while inactivation of the gene in a knockout mouse model increases Aβ formation, suggesting a possible role for this receptor as inhibitor of APP processing and senile plaque formation. A mechanistic model of how SorLA may inhibit amyloidogenic peptide formation was provided by Spoelgen et al., who uncovered a close interaction of SorLA with the β-site APP cleaving enzyme (BACE) inhibiting BACE-APP contact, and hence BACE cleavage of APP (5). Wolfgang Hampe and colleagues now add yet another twist to this story. In this study, they provide evidence that SorLA is a target for intramembrane proteolysis by the γ-secretase complex. Much like APP, SorLA seems to be a substrate of presenilin-dependent proteolytic processing, liberating a short cytoplasmic tail fragment (designated intracellular domain or ICD) that can translocate to the nucleus. As well as with APP, processing of SorLA by γ-secretase requires preceding cleavage of the extracellular domain to produce a short, membrane-anchored receptor fragment that acts as a substrate for the γ-secretase complex. In the case of SorLA, such ectodomain shedding seems to be accomplished by the metalloprotease TACE (7,8). Thus, SorLA is another name on the growing list of membrane proteins that are targets of γ-secretase activity, highlighting the overall biological importance of regulated intramembrane proteolysis. In targets such as APP or Notch, the ICD acts as transcriptional regulator transducing signals from plasma membrane to nucleus. So far, no firm evidence has been provided as to the physiological significance of SorLA cleavage, and whether or not cleavage affects its function as negative regulator of APP processing and Aβ formation. Nevertheless, this new study further emphasizes the importance of this neuronal receptor that functionally interacts with several key components of the amyloidogenic pathway including APP, BACE, and γ-secretase.

References:
1. Scherzer CR, Offe K, Gearing M, Rees HD, Fang G, Heilman CJ, Schaller C, Bujo H, Levey AI, Lah JJ. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004 Aug;61(8):1200-5. Abstract

2. Andersen OM, Schmidt V, Spoelgen R, Gliemann J, Behlke J, Galatis D, McKinstry WJ, Parker MW, Masters CL, Hyman BT, Cappai R, Willnow TE. Molecular Dissection of the Interaction between Amyloid Precursor Protein and Its Neuronal Trafficking Receptor SorLA/LR11. Biochemistry. 2006 Feb 28;45(8):2618-2628. Abstract

3. Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X, Bales KR, Cappai R, Masters CL, Gliemann J, Mufson EJ, Hyman BT, Paul SM, Nykjaer A, Willnow TE. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13461-6. Epub 2005 Sep 7. Abstract

4. Offe K, Dodson SE, Shoemaker JT, Fritz JJ, Gearing M, Levey AI, Lah JJ. The lipoprotein receptor LR11 regulates amyloid beta production and amyloid precursor protein traffic in endosomal compartments. J Neurosci. 2006 Feb 1;26(5):1596-603. Abstract

5. Spoelgen R, von Arnim CA, Thomas AV, Peltan ID, Koker M, Deng A, Irizarry MC, Andersen OM, Willnow TE, Hyman BT. Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme. J Neurosci. 2006 Jan 11;26(2):418-28. Abstract

6. Bohm C, Seibel N, Henkel B, Steiner H, Haass C, Hampe W. SorLA signaling by regulated intramembrane proteolysis. J Biol Chem. 2006 Mar 10; [Epub ahead of print] Abstract

7. Hampe W, Riedel IB, Lintzel J, Bader CO, Franke I, Schaller HC. Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator. J Cell Sci. 2000 Dec;113 Pt 24:4475-85. Abstract

8. Hermey G, Sjogaard S, Petersen CM, Nykjaer A, Gliemann J. Tumour necrosis factor-alpha convertase mediates ectodomain shedding of Vps10p-domain receptor family members. Biochem J. 2006 Jan 4; [Epub ahead of print] Abstract

View all comments by Thomas Willnow

In this article, Bohm et al. demonstrate that the multifunctional mosaic receptor SorLA can be processed by γ-secretase to generate a SorLA cytoplasmic domain. The cleavage of SorLA is analogous to Notch processing and adds a new receptor to the growing number of γ-secretase substrates.

Of particular interest is the finding that the cytoplasmic domain of SorLA migrates to the nucleus and a reporter gene assay suggests a role of SorLA's cytoplasmic domain in transcriptional regulation.

Although the authors found evidence for a signaling function of SorLA and γ-secretase, it still remains unclear whether the function of the cleavage is mainly to degrade membrane-spanning proteins such as SorLA or whether the γ-secretase initiates signal transduction pathways by generating potential transcription factors.

Since previous studies demonstrated that SorLA levels are reduced in the brain of Alzheimer disease patients, Bohm et al. propose a model in which SorLA might compete with APP for γ-secretase cleavage. The relative absence of the receptor in Alzheimer patients could...  Read more

In this article, Bohm et al. demonstrate that the multifunctional mosaic receptor SorLA can be processed by γ-secretase to generate a SorLA cytoplasmic domain. The cleavage of SorLA is analogous to Notch processing and adds a new receptor to the growing number of γ-secretase substrates.

Of particular interest is the finding that the cytoplasmic domain of SorLA migrates to the nucleus and a reporter gene assay suggests a role of SorLA's cytoplasmic domain in transcriptional regulation.

Although the authors found evidence for a signaling function of SorLA and γ-secretase, it still remains unclear whether the function of the cleavage is mainly to degrade membrane-spanning proteins such as SorLA or whether the γ-secretase initiates signal transduction pathways by generating potential transcription factors.

Since previous studies demonstrated that SorLA levels are reduced in the brain of Alzheimer disease patients, Bohm et al. propose a model in which SorLA might compete with APP for γ-secretase cleavage. The relative absence of the receptor in Alzheimer patients could therefore lead to increased cleavage of APP and to elevated Aβ peptide production in patients.

In addition to the potential role of SorLA as a competitive substrate of γ-secretase, our own studies suggest that SorLA directly influences APP processing by directing APP into compartments that are less favorable for Aβ peptide production. Overall, it is striking that a few APP-influencing proteins share very specific pathways and interaction partners.

View all comments by Robert Spoelgen

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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