Journal
ACTA NEUROPATHOLOGICA
Volume 132, Issue 5, Pages 653-665Publisher
SPRINGER
DOI: 10.1007/s00401-016-1615-4
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Funding
- European Research Council (BeyOND)
- Berlin Institute of Health
- Helmholtz Association (International Research Group Program)
- Helmholtz Association (iCEMED)
- Danish National Research council
- Lundbeck Foundation
- Novo Nordisk Foundation
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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.
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