publication . Article . Other literature type . 2016

The amyloid hypothesis of Alzheimer's disease at 25 years

Selkoe, Dennis J; Hardy, John;
Open Access English
  • Published: 29 Mar 2016 Journal: EMBO Molecular Medicine, volume 8, issue 6, pages 595-608 (issn: 1757-4676, eissn: 1757-4684, Copyright policy)
  • Publisher: John Wiley and Sons Inc.
  • Country: United States
Abstract
Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teen...
Subjects
Medical Subject Headings: mental disorders
free text keywords: Review, Aβ, Alzheimer, genetics, cell biology, treatment, Neuroscience, Molecular Medicine, Alzheimer's disease, medicine.disease, medicine, Immunology, Presenilin, Amyloid, Crenezumab, Amyloid precursor protein, biology.protein, biology, Aducanumab, P3 peptide, Biochemistry of Alzheimer's disease
Funded by
WT
Project
  • Funder: Wellcome Trust (WT)
,
NIH| Presenilin Biology and the Mechanism of Alzheimers Disease
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P01AG015379-11
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| Aging in the Brain: The Role of the Fibrous Proteins
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R37AG006173-24
  • Funding stream: NATIONAL INSTITUTE ON AGING
130 references, page 1 of 9

Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X et al (2005) Neuronal sorting protein‐related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102: 13461–13466 16174740 [OpenAIRE] [PubMed]

Andrews‐Zwilling Y, Bien‐Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX, Chen L, Huang Y (2010) Apolipoprotein E4 causes age‐ and Tau‐dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci 30: 13707–13717 20943911 [OpenAIRE] [PubMed]

Ayutyanont N, Langbaum JB, Hendrix SB, Chen K, Fleisher AS, Friesenhahn M, Ward M, Aguirre C, Acosta‐Baena N, Madrigal L et al (2014) The Alzheimer's prevention initiative composite cognitive test score: sample s ize estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. J Clin Psychiatry 75: 652–660 24816373 [OpenAIRE] [PubMed]

Bai XC, Yan C, Yang G, Lu P, Ma D, Sun LD, Zhou R, Scheres SH, Shi Y (2015) An atomic structure of human gamma‐secretase. Nature 535: 212–217 26280335 [OpenAIRE] [PubMed]

Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson‐Wood K et al (2000) Peripherally administered antibodies against amyloid beta‐peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6: 916–919 10932230 [PubMed]

Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM (2006) Human amyloid‐beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12: 856–861 16799555 [OpenAIRE] [PubMed]

Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM et al (2012) Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 367: 795–804 22784036 [OpenAIRE] [PubMed]

Benilova I, Gallardo R, Ungureanu AA, Castillo Cano V, Snellinx A, Ramakers M, Bartic C, Rousseau F, Schymkowitz J, De Strooper B (2014) The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid‐beta (Abeta) aggregation. J Biol Chem 289: 30977–30989 25253695 [OpenAIRE] [PubMed]

Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I et al (2008) Genome‐wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet 83: 623–632 18976728 [OpenAIRE] [PubMed]

Beyreuther K, Masters CL (1991) Amyloid precursor protein (APP) and beta A4 amyloid in the etiology of Alzheimer's disease: precursor‐product relationships in the derangement of neuronal function. Brain Pathol 1: 241–251 1669714 [PubMed]

Blennow K, Mattsson N, Scholl M, Hansson O, Zetterberg H (2015) Amyloid biomarkers in Alzheimer's disease. Trends Pharmacol Sci 36: 297–309 25840462 [PubMed]

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer‐related changes. Acta Neuropathol 82: 239–259 1759558 [PubMed]

Brown P, Gibbs CJ, Rodgers‐Johnson P, Asher DM, Sulima MP, Bacote A, Goldfarb LG, Gajdusek DC (1994) Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 35: 513–529 8179297 [PubMed]

Castellano JM, Kim J, Stewart FR, Jiang H, Demattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C et al (2011) Human apoE isoforms differentially regulate brain amyloid‐β peptide clearance. Sci Transl Med 3, 89ra57.

Chavez‐Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H et al (2012) The mechanism of gamma‐Secretase dysfunction in familial Alzheimer disease. EMBO J 31: 2261–2274 22505025 [OpenAIRE] [PubMed]

130 references, page 1 of 9
Abstract
Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teen...
Subjects
Medical Subject Headings: mental disorders
free text keywords: Review, Aβ, Alzheimer, genetics, cell biology, treatment, Neuroscience, Molecular Medicine, Alzheimer's disease, medicine.disease, medicine, Immunology, Presenilin, Amyloid, Crenezumab, Amyloid precursor protein, biology.protein, biology, Aducanumab, P3 peptide, Biochemistry of Alzheimer's disease
Funded by
WT
Project
  • Funder: Wellcome Trust (WT)
,
NIH| Presenilin Biology and the Mechanism of Alzheimers Disease
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2P01AG015379-11
  • Funding stream: NATIONAL INSTITUTE ON AGING
,
NIH| Aging in the Brain: The Role of the Fibrous Proteins
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R37AG006173-24
  • Funding stream: NATIONAL INSTITUTE ON AGING
130 references, page 1 of 9

Andersen OM, Reiche J, Schmidt V, Gotthardt M, Spoelgen R, Behlke J, von Arnim CA, Breiderhoff T, Jansen P, Wu X et al (2005) Neuronal sorting protein‐related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A 102: 13461–13466 16174740 [OpenAIRE] [PubMed]

Andrews‐Zwilling Y, Bien‐Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX, Chen L, Huang Y (2010) Apolipoprotein E4 causes age‐ and Tau‐dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci 30: 13707–13717 20943911 [OpenAIRE] [PubMed]

Ayutyanont N, Langbaum JB, Hendrix SB, Chen K, Fleisher AS, Friesenhahn M, Ward M, Aguirre C, Acosta‐Baena N, Madrigal L et al (2014) The Alzheimer's prevention initiative composite cognitive test score: sample s ize estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers. J Clin Psychiatry 75: 652–660 24816373 [OpenAIRE] [PubMed]

Bai XC, Yan C, Yang G, Lu P, Ma D, Sun LD, Zhou R, Scheres SH, Shi Y (2015) An atomic structure of human gamma‐secretase. Nature 535: 212–217 26280335 [OpenAIRE] [PubMed]

Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson‐Wood K et al (2000) Peripherally administered antibodies against amyloid beta‐peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6: 916–919 10932230 [PubMed]

Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM (2006) Human amyloid‐beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12: 856–861 16799555 [OpenAIRE] [PubMed]

Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM et al (2012) Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med 367: 795–804 22784036 [OpenAIRE] [PubMed]

Benilova I, Gallardo R, Ungureanu AA, Castillo Cano V, Snellinx A, Ramakers M, Bartic C, Rousseau F, Schymkowitz J, De Strooper B (2014) The Alzheimer disease protective mutation A2T modulates kinetic and thermodynamic properties of amyloid‐beta (Abeta) aggregation. J Biol Chem 289: 30977–30989 25253695 [OpenAIRE] [PubMed]

Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, Divito J, Ionita I et al (2008) Genome‐wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE. Am J Hum Genet 83: 623–632 18976728 [OpenAIRE] [PubMed]

Beyreuther K, Masters CL (1991) Amyloid precursor protein (APP) and beta A4 amyloid in the etiology of Alzheimer's disease: precursor‐product relationships in the derangement of neuronal function. Brain Pathol 1: 241–251 1669714 [PubMed]

Blennow K, Mattsson N, Scholl M, Hansson O, Zetterberg H (2015) Amyloid biomarkers in Alzheimer's disease. Trends Pharmacol Sci 36: 297–309 25840462 [PubMed]

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer‐related changes. Acta Neuropathol 82: 239–259 1759558 [PubMed]

Brown P, Gibbs CJ, Rodgers‐Johnson P, Asher DM, Sulima MP, Bacote A, Goldfarb LG, Gajdusek DC (1994) Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 35: 513–529 8179297 [PubMed]

Castellano JM, Kim J, Stewart FR, Jiang H, Demattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C et al (2011) Human apoE isoforms differentially regulate brain amyloid‐β peptide clearance. Sci Transl Med 3, 89ra57.

Chavez‐Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H et al (2012) The mechanism of gamma‐Secretase dysfunction in familial Alzheimer disease. EMBO J 31: 2261–2274 22505025 [OpenAIRE] [PubMed]

130 references, page 1 of 9
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