13 Mar 2015

Genome-wide association studies have uncovered more than 20 genes that are linked to Alzheimer’s, but scientists have struggled to discover how the potential risk variants actually contribute to disease. Now, in the April 2 Cell Stem Cell, researchers led by Lawrence Goldstein at the University of California San Diego present one promising approach to this puzzle. The authors used induced pluripotent stem (iPS) cells generated from AD patients and controls to examine polymorphisms in the risk factor SORL1. SORL1 blocks the processing of amyloid precursor protein into Aβ. The authors found that induced neurons carrying a protective variant dialed up SORL1 expression in response to a neurotrophic factor, and subsequently made less Aβ than did cells lacking the protective allele. This suggests a mechanism by which these variants may modulate AD risk, the authors conclude. “The data highlight the power of using patient-derived stem cells to study the molecular and cell biology behind the complex risk factors that play into sporadic AD,” first author Jessica Young told Alzforum.

Ekaterina Rogaeva at the University of Toronto, who helped discover the link between SORL1 and AD, called the study elegant and exciting. “It opens up many avenues for future research. I would be curious if other SORL1 risk variants follow the same mechanism they discovered here.” She noted, however, that due to the small number of cell lines used, the findings need to be confirmed by replication.

SORL1, which also goes by SorLA and LR11, is a sorting receptor that occupies endosomes and interacts with APP and Aβ. Several genetic studies have turned up numerous AD risk variants around this gene, and there are hints some polymorphisms may even cause an early onset form of the disease (see Alzgene entry; Jan 2007 news; Apr 2012 news). Meanwhile, cellular studies report that the receptor sorts APP away from amyloidogenic processing, and in addition can direct Aβ to lysosomes for destruction (see Mar 2005 conference story; Feb 2014 news).

This history made SORL1 a good candidate to examine in iPS cells, Young said. She generated iPSC lines from seven AD patients and six age-matched controls, and genotyped the cells for three SNPs at the 5’ end of the gene. These are inherited together as either a risk (R) or a protective (P) haplotype (see Rogaeva et al., 2007). While the SNPs tag the two haplotypes, they are probably not the functional polymorphism, Young noted. Both haplotypes were about equally represented in the 13 cell lines, leading to three P/P lines, six R/P, and four R/R. To the authors’ surprise, however, the haplotypes did not correlate with basal SORL1 expression in induced neurons.

For clues to the mechanism behind the increased AD risk, Young turned to a previous study by Thomas Willnow and colleagues in Germany, which had reported that brain-derived neurotrophic factor (BDNF) induced the expression of the mouse SORL1 homolog (see Dec 2009 news). How would the different haplotypes respond to this neurotrophin? Young added BDNF to her cultures, and found that neurons from the nine cell lines that carried at least one protective haplotype boosted SORL1 expression by about 50 percent, whereas the four lines that were homozygous for the risk variants did not. Likewise, Aβ40 levels dropped by about 20 percent in the nine lines with protective polymorphisms, but did not budge in the other four. Knockdown of SORL1 prevented the drop in Aβ after BDNF treatment, while overexpression of the receptor suppressed amyloid production even in R/R cells. This demonstrated that BDNF reduces Aβ by boosting SORL1.

The modest effect on Aβ is consistent with the role of these alleles as risk factors, Young noted. Between 30 percent and 50 percent of the population carry two risk alleles, but this genotype heightens the odds of developing AD by only about 30 percent, she said. Hence, not everyone who carries these alleles will necessarily develop AD. In keeping with this, risk and protective alleles did not correlate with clinical diagnosis in her samples; two of the cell lines with protective alleles came from AD patients, while two of the homozygous risk lines came from cognitively healthy people. Other genetic and environmental factors likely come into play to determine who will develop the disease, she said.

In future studies, Young will examine the effect of other SORL1 variants, including some rare mutations linked to familial disease. Because these occur in very few patients, she will introduce the mutations to her cell lines through genome editing. Rogaeva suggested it would be worthwhile to study the relatively common coding variant A528T, which is present in 15 percent of people, segregates with disease within families, and directly alters Aβ levels (see Vardarajan et al., 2015).

One day, the iPSC system might allow clinicians to predict which patients will respond best to particular therapies, Young suggested. For example, based on the current study, patients carrying at least one protective 5’ SORL1 allele would be most likely to benefit from a BDNF-based therapy. This knowledge could help screen patients for clinical trials.—Madolyn Bowman Rogers

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References

Alzpedia Citations

1. SORLA (SORL1)

News Citations

1. SORLA Soars—Large Study Links Gene to Late-onset AD 15 Jan 2007
2. New Genetic Insights Into AD: SORL1 and Natural Selection 6 Apr 2012
3. Sorrento: Sorting Out Shedding of Ectodomains 24 Mar 2005
4. SORLA Serves Up Aβ for Destruction 14 Feb 2014
5. Traffic Control: BDNF Boosts SORLA, Reroutes APP 11 Dec 2009

Paper Citations

1. Rogaeva E, Meng Y, Lee JH, Gu Y, Kawarai T, Zou F, Katayama T, Baldwin CT, Cheng R, Hasegawa H, Chen F, Shibata N, Lunetta KL, Pardossi-Piquard R, Bohm C, Wakutani Y, Cupples LA, Cuenco KT, Green RC, Pinessi L, Rainero I, Sorbi S, Bruni A, Duara R, Friedland RP, Inzelberg R, Hampe W, Bujo H, Song YQ, Andersen OM, Willnow TE, Graff-Radford N, Petersen RC, Dickson D, Der SD, Fraser PE, Schmitt-Ulms G, Younkin S, Mayeux R, Farrer LA, St George-Hyslop P. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007 Feb;39(2):168-77. PubMed.
2. Vardarajan BN, Zhang Y, Lee JH, Cheng R, Bohm C, Ghani M, Reitz C, Reyes-Dumeyer D, Shen Y, Rogaeva E, St George-Hyslop P, Mayeux R. Coding mutations in SORL1 and Alzheimer disease. Ann Neurol. 2015 Feb;77(2):215-27. PubMed.

External Citations

1. Alzgene entry

Further Reading

News

1. Voilà SorLA! Sorting Receptor’s Structure Solved 6 Feb 2015
2. Coming Into Vogue? Retromer in APP Processing, AD Pathogenesis 15 Jun 2012
3. Aβ and SORLA—Partners in Cerebrovascular Crime? 19 Dec 2008
4. Mice, Flies Further Implicate Retromer in AD Pathogenesis 12 May 2008
5. Keystone: Probing the Function of Lipoprotein and Related Receptors 28 Mar 2012
6. Sorting Out SorLA—What Role in APP Processing, AD? 25 Sep 2007
7. Induced Neurons From AD Patients Hint at Disease Mechanisms 31 Jan 2012
8. Where in the World Are the iPS Cells? 15 Sep 2010