Current and future implications of basic and translational research on amyloid-β peptide production and removal pathways.
Inherited variants in multiple different genes are associated with increased risk for Alzheimer's disease (AD). In many of these genes, the inherited variants alter some aspect of the production or clearance of the neurotoxic amyloid β-peptide (Aβ). Thus missense, splice site or duplication mutants in the presenilin 1 (PS1), presenilin 2 (PS2) or the amyloid precursor protein (APP) genes, which alter the levels or shift the balance of Aβ produced, are associated with rare, highly penetrant autosomal dominant forms of Familial Alzheimer's Disease (FAD). Similarly, the more prevalent late-onset forms of AD are associated with both coding and non-coding variants in genes such as SORL1, PICALM and ABCA7 that affect the production and clearance of Aβ. This review summarises some of the recent molecular and structural work on the role of these genes and the proteins coded by them in the biology of Aβ. We also briefly outline how the emerging knowledge about the pathways involved in Aβ generation and clearance can be potentially targeted therapeutically. This article is part of Special Issue entitled "Neuronal Protein".
Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Krembil Discovery Tower, 6th Floor-6KD417, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.
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Bohm
Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Krembil Discovery Tower, 6th Floor-6KD417, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.
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Chen
Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Krembil Discovery Tower, 6th Floor-6KD417, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.
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Sevalle
Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 0XY, UK.
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Qamar
Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 0XY, UK.
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Dodd
Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 0XY, UK.
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Li
Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Krembil Discovery Tower, 6th Floor-6KD417, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.
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Schmitt-Ulms
Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Krembil Discovery Tower, 6th Floor-6KD417, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada.
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Fraser
Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Krembil Discovery Tower, 6th Floor-6KD417, 60 Leonard Avenue, Toronto, Ontario M5T 2S8, Canada; Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Addenbrookes Hospital, Hills Road, Cambridge CB2 0XY, UK. Electronic address: phs22@cam.ac.uk.
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St George-Hyslop
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*; D057170:Translational Research, Biomedical
D016229:Amyloid beta-Peptides
APOE; APP; Abeta; Alzheimer; Amyloid; Dementia; EPHA1; Genetics; Neurodegeneration; Next generation sequencing; Nicastrin; PICALM; PSEN1; Presenilin; SORL1; Secretase; Tau; Vaccine