The endocytotic pathway is required for increased A beta 42 secretion during apoptosis.
Secretion and progressive cerebral accumulation of beta-amyloid peptides (A beta), which derive by endoproteolytic ('amyloidogenic') processing of beta-amyloid precursor protein (APP), are felt to represent collectively an early and necessary event in the pathogenesis of Alzheimer's disease. APP amyloidogenic processing can occur via secretory or endocytotic pathways, but the relative contribution of these pathways to A beta secretion remains to be established. The effect of apoptosis on amyloidogenic processing and A beta secretion similarly is incompletely understood. We tested the hypothesis that APP processing by the endocytotic pathway represents a stress-related neural cell response, by comparing A beta secretion after induction of apoptosis in PC12 cells transfected either for endocytosis-competent or -deficient APP. Newly prepared adenoviral vectors encompassing targeted mutagenesis of the cytoplasmic tail YENP tetrapeptide sequence, which serves as the principal APP internalization signal, were used to express endocytosis-deficient holoprotein. We report that the endocytotic pathway is required for the generation and secretion of A beta 42, and that secretion of this neurotoxic peptide increases significantly during apoptosis. We demonstrate additionally that more A beta 40 apparently is generated in secretory compartments during apoptosis when APP processing by the endocytotic pathway is impaired.
Sodhi
Chhinder P
CP
Department of Pathology, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, IL 60611, USA.
Rampalli
Srinivas
S
Perez
Ruth G
RG
Koo
Edward H
EH
Quinn
Bruce
B
Gottardi-Littell
Numa R
NR
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D004705:Endocytosis / Q000502:physiology*; D010450:Endopeptidases; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D019311:Staurosporine / Q000009:adverse effects; D013997:Time Factors; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017304:Annexin A5; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; D019311:Staurosporine