PMID- 37355492
OWN - NLM
STAT- MEDLINE
DCOM- 20230905
LR  - 20230907
IS  - 1573-6830 (Electronic)
IS  - 0272-4340 (Print)
IS  - 0272-4340 (Linking)
VI  - 43
IP  - 7
DP  - 2023 Oct
TI  - APP-BACE1 Interaction and Intracellular Localization Regulate Abeta Production in 
      iPSC-Derived Cortical Neurons.
PG  - 3653-3668
LID - 10.1007/s10571-023-01374-0 [doi]
AB  - Alzheimer's disease (AD) is characterized pathologically by amyloid beta 
      (Abeta)-containing plaques. Generation of Abeta from amyloid precursor protein (APP) by 
      two enzymes, beta- and gamma-secretase, has therefore been in the AD research spotlight 
      for decades. Despite this, how the physical interaction of APP with the 
      secretases influences APP processing is not fully understood. Herein, we compared 
      two genetically identical human iPSC-derived neuronal cell types: low 
      Abeta-secreting neuroprogenitor cells (NPCs) and high Abeta-secreting mature neurons, 
      as models of low versus high Abeta production. We investigated levels of substrate, 
      enzymes and products of APP amyloidogenic processing and correlated them with the 
      proximity of APP to beta- and gamma-secretase in endo-lysosomal organelles. In mature 
      neurons, increased colocalization of full-length APP with the beta-secretase BACE1 
      correlated with increased beta-cleavage product sAPPbeta. Increased flAPP/BACE1 
      colocalization was mainly found in early endosomes. In the same way, increased 
      colocalization of APP-derived C-terminal fragment (CTF) with presenilin-1 
      (PSEN1), the catalytic subunit of gamma-secretase, was seen in neurons as compared to 
      NPCs. Furthermore, most of the interaction of APP with BACE1 in low Abeta-secreting 
      NPCs seemed to derive from CTF, the remaining APP part after BACE1 cleavage, 
      indicating a possible novel product-enzyme inhibition. In conclusion, our results 
      suggest that interaction of APP and APP cleavage products with their secretases 
      can regulate Abeta production both positively and negatively. beta- and gamma-Secretases 
      are difficult targets for AD treatment due to their ubiquitous nature and wide 
      range of substrates. Therefore, targeting APP-secretase interactions could be a 
      novel treatment strategy for AD. Colocalization of APP species with BACE1 in a 
      novel model of low- versus high-Abeta secretion-Two genetically identical human 
      iPSC-derived neuronal cell types: low Abeta-secreting neuroprogenitor cells (NPCs) 
      and high Abeta secreting mature neurons, were compared. Increased full-length APP 
      (flAPP)/BACE1 colocalization in early endosomes was seen in neurons, while 
      APP-CTF/BACE1 colocalization was much higher than flAPP/BACE1 colocalization in 
      NPCs, although the cellular location was not determined.
CI  - (c) 2023. The Author(s).
FAU - Roselli, Sandra
AU  - Roselli S
AUID- ORCID: 0000-0003-2998-3760
AD  - Institute of Neuroscience and Physiology, Department of Psychiatry and 
      Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Bla 
      Straket 15, Sahlgrenska Hospital, 405 30, Gothenburg, Sweden. 
      sandra.roselli@gu.se.
FAU - Satir, Tugce Munise
AU  - Satir TM
AUID- ORCID: 0000-0001-9021-1650
AD  - Institute of Neuroscience and Physiology, Department of Psychiatry and 
      Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Bla 
      Straket 15, Sahlgrenska Hospital, 405 30, Gothenburg, Sweden.
FAU - Camacho, Rafael
AU  - Camacho R
AUID- ORCID: 0000-0003-2325-6407
AD  - Centre for Cellular Imaging, Core Facilities, The Sahlgrenska Academy, University 
      of Gothenburg, Medicinaregatan 7A, 405 30, Gothenburg, Sweden.
FAU - Fruhwurth, Stefanie
AU  - Fruhwurth S
AUID- ORCID: 0000-0003-4035-7330
AD  - Institute of Neuroscience and Physiology, Department of Psychiatry and 
      Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Bla 
      Straket 15, Sahlgrenska Hospital, 405 30, Gothenburg, Sweden.
FAU - Bergstrom, Petra
AU  - Bergstrom P
AUID- ORCID: 0000-0003-1803-165X
AD  - Institute of Neuroscience and Physiology, Department of Psychiatry and 
      Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Bla 
      Straket 15, Sahlgrenska Hospital, 405 30, Gothenburg, Sweden.
FAU - Zetterberg, Henrik
AU  - Zetterberg H
AUID- ORCID: 0000-0003-3930-4354
AD  - Institute of Neuroscience and Physiology, Department of Psychiatry and 
      Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Bla 
      Straket 15, Sahlgrenska Hospital, 405 30, Gothenburg, Sweden.
AD  - Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Building V3, 
      Molndal Hospital, 431 80, Molndal, Sweden.
AD  - Department of Neurodegenerative Disease, Institute of Neurology, University 
      College London Queen Square, Queen Square, London, WC1N 3BG, UK.
AD  - UK Dementia Research Institute at UCL, Cruciform Building, Gower Street, London, 
      WC1E 6BT, UK.
AD  - Hong Kong Center for Neurodegenerative Diseases, Units 1501-1502, 1512-1518, 
      15/F, Building 17W, Hong Kong Science Park, Shatin, N.T., Hong Kong, China.
AD  - Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of 
      Medicine and Public Health, University of Wisconsin-Madison, 600 Highland Avenue, 
      Madison, WI, 53792, USA.
FAU - Agholme, Lotta
AU  - Agholme L
AUID- ORCID: 0000-0003-3816-7474
AD  - Institute of Neuroscience and Physiology, Department of Psychiatry and 
      Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Bla 
      Straket 15, Sahlgrenska Hospital, 405 30, Gothenburg, Sweden.
LA  - eng
GR  - 681712/ERC_/European Research Council/International
PT  - Journal Article
DEP - 20230624
PL  - United States
TA  - Cell Mol Neurobiol
JT  - Cellular and molecular neurobiology
JID - 8200709
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Amyloid beta-Peptides)
RN  - EC 3.4.- (Amyloid Precursor Protein Secretases)
RN  - EC 3.4.23.- (Aspartic Acid Endopeptidases)
RN  - EC 3.4.23.46 (BACE1 protein, human)
SB  - IM
MH  - Humans
MH  - Amyloid beta-Protein Precursor
MH  - Amyloid beta-Peptides
MH  - Amyloid Precursor Protein Secretases
MH  - Aspartic Acid Endopeptidases
MH  - *Induced Pluripotent Stem Cells
MH  - *Alzheimer Disease
MH  - Neurons
PMC - PMC10477112
OTO - NOTNLM
OT  - Amyloid beta
OT  - Amyloid precursor protein
OT  - Beta secretase
OT  - Early endosomes
OT  - Gamma secretase
OT  - Neurons
OT  - Proximity ligation assay
COIS- Henrik Zetterberg has served at scientific advisory boards and/or as a consultant 
      for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, 
      Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, 
      Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given 
      lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and 
      Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), 
      which is a part of the GU Ventures Incubator Program. The other authors report no 
      conflicts of interest.
EDAT- 2023/06/25 01:08
MHDA- 2023/09/05 06:42
PMCR- 2023/06/24
CRDT- 2023/06/24 23:03
PHST- 2022/12/08 00:00 [received]
PHST- 2023/06/09 00:00 [accepted]
PHST- 2023/09/05 06:42 [medline]
PHST- 2023/06/25 01:08 [pubmed]
PHST- 2023/06/24 23:03 [entrez]
PHST- 2023/06/24 00:00 [pmc-release]
AID - 10.1007/s10571-023-01374-0 [pii]
AID - 1374 [pii]
AID - 10.1007/s10571-023-01374-0 [doi]
PST - ppublish
SO  - Cell Mol Neurobiol. 2023 Oct;43(7):3653-3668. doi: 10.1007/s10571-023-01374-0. 
      Epub 2023 Jun 24.