Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production

Cláudia Guimas Almeida, Farzaneh Sadat Mirfakhar, Catarina Perdigão, Tatiana Burrinha

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The increased production of the 42 aminoacids long beta-amyloid (Aβ42) peptide has been established as a causal mechanism of the familial early onset Alzheimer’s disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Aβ42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Aβ accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Aβ42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Aβ42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Aβ42. Dissecting causal LOAD mechanisms of Aβ42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies.

Original languageEnglish
Pages (from-to)2577-2589
Number of pages13
JournalCellular and Molecular Life Sciences
Volume75
Issue number14
DOIs
Publication statusPublished - Jul 2018

Fingerprint

Amyloid
Alzheimer Disease
Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Genome-Wide Association Study
Endosomes
Amyloid beta-Peptides
Genes
Therapeutics

Keywords

  • APOE4
  • BIN1
  • CD2AP
  • Endocytosis
  • Late-onset Alzheimer’s disease
  • PICALM
  • PLD3
  • SORL1
  • Trafficking

Cite this

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title = "Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production",
abstract = "The increased production of the 42 aminoacids long beta-amyloid (Aβ42) peptide has been established as a causal mechanism of the familial early onset Alzheimer’s disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Aβ42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Aβ accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Aβ42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Aβ42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Aβ42. Dissecting causal LOAD mechanisms of Aβ42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies.",
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Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production. / Guimas Almeida, Cláudia; Sadat Mirfakhar, Farzaneh; Perdigão, Catarina; Burrinha, Tatiana.

In: Cellular and Molecular Life Sciences, Vol. 75, No. 14, 07.2018, p. 2577-2589.

Research output: Contribution to journalArticle

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