Research ArticleAlzheimer’s Disease

Lysosomal Sorting of Amyloid-β by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation

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Science Translational Medicine  12 Feb 2014:
Vol. 6, Issue 223, pp. 223ra20
DOI: 10.1126/scitranslmed.3007747

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SORLA: Sorting Aβ for Destruction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. The principal cause of AD is neurotoxic amyloid-β (Aβ) peptides, derived by processing of an amyloid precursor protein, which impair neuronal viability and function. Current efforts are directed toward elucidating factors that determine the extent of Aβ production that could represent therapeutic targets to reduce Aβ buildup in the brain. In new work, Caglayan and colleagues focused on SORLA, a sorting receptor genetically associated with both sporadic and familial forms of AD. Because low SORLA levels coincide with high Aβ concentrations in AD patients, the authors tested whether and by what mechanism raising SORLA activity could protect from Aβ peptide accumulation. Using mouse models overexpressing human SORLA, the authors documented that boosting this receptor caused a marked reduction in brain Aβ. The underlying molecular mechanism was traced to the ability of SORLA to direct newly produced Aβ to lysosomes for degradation. The authors also demonstrated that this sorting function was lost in a SORLA receptor carrying a G511R mutation expressed in an autosomal dominant form of AD.

This study substantiates the beneficial effects of raising SORLA activity for AD-related processes, and identifies lysosomal sorting of Aβ as a new pathway that may be amenable to therapeutic intervention.

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