Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout

Author:

Arber Charles1ORCID,Villegas-Llerena Claudio12,Toombs Jamie13,Pocock Jennifer M2,Ryan Natalie S4,Fox Nick C134,Zetterberg Henrik1356,Hardy John13,Wray Selina1

Affiliation:

1. Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK

2. Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK

3. UK Dementia Research Institute at UCL, London, UK

4. Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK

5. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden

6. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

Abstract

Abstract Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme γ-secretase, cause familial Alzheimer’s disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predominantly through gain or loss of function. To address this question, we generated an isogenic allelic series for the PSEN1 mutation intron 4 deletion; represented by control, heterozygous and homozygous mutant induced pluripotent stem cells in addition to a presenilin-1 knockout line. Induced pluripotent stem cell-derived cortical neurons reveal reduced, yet detectable amyloid-beta levels in the presenilin-1 knockout line, and a mutant gene dosage-dependent defect in amyloid precursor protein processing in PSEN1 intron 4 deletion lines, consistent with reduced processivity of γ-secretase. The different effects of presenilin-1 knockout and the PSEN1 intron 4 deletion mutation on amyloid precursor protein-C99 fragment accumulation, nicastrin maturation and amyloid-beta peptide generation support distinct consequences of familial Alzheimer’s disease-associated mutations and knockout of presenilin-1 on the function of γ-secretase.

Funder

National Institute for Health Research University College London Hospitals Biomedical Research Centre

Leonard Wolfson Experimental Neurology Centre

UK Dementia Research Institute

Alzheimer’s Society

Alzheimer’s Research UK Senior Research Fellowship

University of London Chadburn Academic Clinical Lectureship in Medicine

Dementia Research Institute at UCL

UK Medical Research Council

MRC Dementia Platform UK

MRC-UCL LMCB

Publisher

Oxford University Press (OUP)

Subject

General Earth and Planetary Sciences,General Environmental Science

Reference34 articles.

1. Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta;Arber;Mol Psychiatry,2019

2. The mechanism of γ-secretase dysfunction in familial Alzheimer disease;Chávez-Gutiérrez;EMBO J,2012

3. Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer’s disease by increased Abeta42 secretion;De Jonghe;Hum Mol Genet,1999

4. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein;De Strooper;Nature,1998

5. Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex;De Strooper;Neuron,2003

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3