gamma-secretase processing of APLP1 leads to the production of a p3-like peptide that does not aggregate and is not toxic to neurons.
The amyloid precursor-like protein-1 (APLP1) is a member of a protein family that includes the Alzheimer's disease-associated amyloid precursor protein (APP). While much is known about the proteolytic processing of APP, fewer details are available about APLP1. Using Chinese hamster ovarian cells stably transfected with human APLP1 and a novel juxtamembrane anti-APLP1 antibody, we demonstrate the detection of a secreted approximately 3.5 kDa APLP1-derived peptide (ALP-1). The production of this peptide is abolished by inhibition of gamma-secretase, but not beta-secretase, suggesting that ALP-1 is analogous to the p3 fragment produced from APP. However, unlike p3 or Abeta, ALP-1 shows no obvious propensity for aggregation and is not toxic to neuronal cells. Moreover, using two distinct experimental paradigms, we demonstrate that neither cell-derived nor chemically synthesized ALP-1 influences the oligomerization or aggregation of Abeta.
Minogue
Aedín M
AM
Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
Stubbs
Adam K
AK
Frigerio
Carlo Sala
CS
Boland
Barry
B
Fadeeva
Julia V
JV
Tang
Jordan
J
Selkoe
Dennis J
DJ
Walsh
Dominic M
DM
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009498:Neurotoxins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
C489697:APLP1 protein, human; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D017077:Culture Media, Conditioned; D009498:Neurotoxins; D010446:Peptide Fragments; D053829:Amyloid Precursor Protein Secretases