14 Feb 2014

The giant metal claw at a junkyard carries pieces of metal off to be crushed. Could SORLA dispose of Aβ in a similar way? In the February 12 Science Translational Medicine, scientists led by Thomas Willnow, Max-Delbrück-Center for Molecular Medicine, Berlin, and Junichi Takagi, Osaka University, Japan, report that SORLA grabs newly made Aβ in the neuron and steers it toward lysosomes, where it is degraded. A SORLA mutation previously associated with familial Alzheimer’s disease disrupts that binding. “This may be a new intracellular pathway for regulation of Aβ homeostasis,” said Willnow. “Evidence suggests that interference with this pathway may be a novel cause of a familial form of AD.”

“[The paper] ties together two prominent features of AD pathology by proposing a role for SORLA in delivering Aβ to lysosomes,” commented Ralph Nixon, Nathan Kline Institute, Orangeburg, New York. It adds to evidence that has been building for years about the importance of lysosomes in the clearance of Aβ, he said (see Yang et al., 2011). 

SORLA, or sortilin-related receptor with A-type repeats, is an endocytic receptor that binds to APP and shuttles it between Golgi, the cell surface, and endosomes. Also known as SORL1 or LR11, SORLA keeps APP away from secretases that release Aβ. Previous studies have suggested that SORLA plays a role in Alzheimer's pathology. Its expression drops in the brains of people with sporadic AD, and variants in the gene increase the risk for both sporadic and familial forms of the disease (see Scherzer et al., 2004; Rogaeva et al., 2007; and Apr 2005 news story on Pottier et al., 2012). Willnow’s group previously found that loss of SORLA in mice enhanced Aβ production and deposition, while in cell culture, overexpression of SORLA reduced amyloidogenic processing (see Mar 2005 news story and Andersen et al., 2005). 

To find out whether boosting the protein’s expression in vivo has the same effect, first author Safak Caglayan and colleagues generated wild-type and PDAPP mice that overexpressed human SORLA in the cortex and hippocampus (see image below). This gave them about four times the usual level of the protein. The scientists then tracked APP processing and Aβ clearance. Surprisingly, the former remained steady, with levels of sAPPα and sAPPβ fragments matching those from control mice. Even so, Aβ40 and Aβ42 in brain extracts fell by at least half in both wild-type and PDAPP mice. Curiously, Aβ in the brain interstitial fluid did not budge. What could explain the drop in Aβ in brain extracts? 

SORLA sports a motif called a VPS10P domain. Since other receptors use VPS10P to  guide proteins to the lysosome, the authors hypothesized that SORLA might do the same for Aβ. Sure enough, an in-vitro fluorescence polarization assay that detected transient protein-peptide interactions confirmed that SORLA’s VPS10P domain bound to Aβ40’s Aβ6-20 region. At a pH lower than 5.0 the connection broke, implying that it dissociates in acidic environments such as those found in lysosomes. Caglayan next checked the hypothesis in neuron-like cells. In neuroblastoma cells expressing APP695, lysosomes bore twice the amount of Aβ, but it also disappeared faster from the cells when they produced SORLA. To find out if mutations changed this, the authors examined a human embryonic kidney cell line containing SORLA with the G511R mutation, a variant in the VPS10P domain that has been associated with early onset AD. In these cells, SORLA did not interact with Aβ and the peptide cleared more slowly than usual.

“This is an interesting paper by a group that has done top-level work on SORLA biology,” said Gunnar Gouras, Lund University, Sweden. He noted that the G511R mutation is linked with Alzheimer’s disease, but affects intracellular rather than secreted Aβ. This further supports the long-held, albeit still controversial, idea that intraneuronal Aβ causes problems for neurons, he said (see Dec 2005 news story; Jun 2011 live discussion). Gouras is curious to see whether a boost in SORLA improves synaptic physiology or behavior in mice. His group previously found that synaptic activity drives secretion of Aβ, but less so as cells age, suggesting that failure to rid themselves of intraneuronal Aβ harms older neurons (see Nov 2011 news story on Tampellini et al., 2011). 

Caglayan and colleagues wondered why quadrupling the SORLA in mice failed to reduce APP processing. It could be that the mice had already expressed enough of their own protein, so more SORLA provided no further benefit, the authors proposed. Scott Small, Columbia University, New York, noted that a trend toward lower levels of APP fragments in PDAPP mice did hint at some effect. 

Jeremy Herskowitz, Emory University, Atlanta, agreed, and cautioned that it is difficult to distinguish between effects on APP processing and direct effects on Aβ. Nevertheless, both remarked that the authors present an interesting hypothesis that may shed light on another role for SORLA. 

Does this finding point to a potential therapy for AD? In 2009, Willnow and others demonstrated that brain-derived neurotrophic factor (BDNF) boosts SORLA levels in mouse neurons and reduces Aβ (see Dec 2009 news story). Levels of BDNF fall in Alzheimer’s patients (see Murray et al., 1994) and BDNF improves learning and memory of animal models of AD (see Feb 2009 news story). “Part of BDNF’s beneficial effect could arise because it upregulates this protective factor, SORLA,” Willnow speculated.  His group will next screen compound libraries for small molecules that upregulate SORLA in neurons.—Gwyneth Dickey Zakaib

 

Comments

1. • Frédéric Checler
     Institut de Pharmacologie Moléculaire et Cellulaire
   • Posted: 14 Feb 2014
   • Paper: Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation.

   This is an important paper. It appears as one of very few examples of delineated risk factors for AD for which a plausible function linked to Aβ degradation is clearly documented. Of most interest, obviously, is the observation that an AD-linked mutation could directly impair the Aβ-SORLA interaction and lead to enhanced Aβ levels, thereby bringing a biological rational for the original genetic observation. This adds a bit more support to the amyloid cascade hypothesis. In sporadic AD, there are no clues of enhanced Aβ formation. Rather, it is the decrease of degradation rates that leads to increased cerebral loads of peptides.

   This paper further supports the view that Aβ levels are modulated downstream of secretase actions. Both SORLA levels that are diminished in sporadic AD-affected brains and mechanisms of action of SORLA support the view that this receptor contributes to sporadic AD. The fact that the mutation the authors examined, located in the SORLA domain that interacts with Aβ, affects SORLA function is interesting. The question to address is whether other SORLA mutations located outside this VPS10P domain trigger the same effect. It is possible that mutations outside the binding domain could alter the 3-D structure to ultimately affect lysosomal Aβ degradation. Alternatively, it remains possible that additional AD-linked mutations enhance AD risk by affecting other pathways, even unrelated to APP trafficking/processing.

   View all comments by Frédéric Checler

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References

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1. SORLA (SORL1)

News Citations

1. New Genetic Insights Into AD: SORL1 and Natural Selection 6 Apr 2012
2. Sorrento: Sorting Out Shedding of Ectodomains 24 Mar 2005
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1. PDAPP(line109)

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1. Intraneuronal Aβ: Was It APP All Along? 20 Jun 2011

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External Citations

1. gene

Further Reading

News

1. Pooled GWAS Reveals New Alzheimer’s Genes and Pathways 26 Jul 2013