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Risk factor SORL1: from genetic association to functional validation in Alzheimer's disease

Authors

  • O.M. Andersen
  • I.M. Rudolph
  • T.E. Willnow

Journal

  • Acta Neuropathologica

Citation

  • Acta Neuropathol 132 (5): 653-665

Abstract

  • Alzheimer's disease (AD) represents one of the most dramatic threats to healthy aging and devising effective treatments for this devastating condition remains a major challenge in biomedical research. Much has been learned about the molecular concepts that govern proteolytic processing of the amyloid precursor protein to amyloid-{beta} peptides (A{beta}), and how accelerated accumulation of neurotoxic A{beta} peptides underlies neuronal cell death in rare familial but also common sporadic forms of this disease. Out of a plethora of proposed modulators of amyloidogenic processing, one protein emerged as a key factor in AD pathology, a neuronal sorting receptor termed SORLA. Independent approaches using human genetics, clinical pathology, or exploratory studies in animal models all converge on this receptor that is now considered a central player in AD-related processes by many. This review will provide a comprehensive overview of the evidence implicating SORLA-mediated protein sorting in neurodegenerative processes, and how receptor gene variants in the human population impair functional receptor expression in sporadic but possibly also in autosomal-dominant forms of AD.


DOI

doi:10.1007/s00401-016-1615-4