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Intracellularly generated amyloid-beta peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells.
J Neurochem. 2004 Dec; 91(6):1260-74.JN

Abstract

Most mutations in amyloid precursor proteins (APPs) linked to early onset familial Alzheimer's disease (FAD) increase the production of amyloid-beta peptides ending at residue 42 (Abeta42), which are released from APP by beta- and gamma-secretase cleavage. Stably transfected cells expressing wild-type human APP (APP(WT)) were more resistant to apoptosis-inducing treatments than cells expressing FAD-mutant human APP (APP(FAD)). Preventing Abeta42 production with an M596I mutation (beta-), which blocks beta-secretase cleavage of APP, or by treatment with a gamma-secretase inhibitor increased the resistance of APP(FAD)-expressing cells to apoptosis. Exposing hAPP(FAD/beta-) cells to exogenous Abeta42 or conditioned medium from Abeta42-producing APP(FAD) cells did not diminish their resistance to apoptosis. Preventing APP from entering the distal secretory pathway, where most Abeta peptides are generated, by retaining APP in the endoplasmic reticulum (ER)/intermediate compartment (IC) increased the resistance of APP(FAD)-expressing cells to apoptosis and did not alter the resistance of APP(WT)-expressing cells. p53-mediated gene transactivation after apoptosis-inducing treatments was much stronger in APP(FAD) cells than in hAPP(WT) or hAPP(FAD/beta-) cells. In contrast, upon induction of ER stress, cells expressing APP(FAD), hAPP(FAD/beta-), or APP(WT) had comparable levels of glucose-regulated protein-78 mRNA, an unfolded protein response indicator. We conclude that Abeta, especially intracellular Abeta, counteracts the antiapoptotic function of its precursor protein and predisposes cells to p53-mediated, and possibly other, proapoptotic pathways.

Authors+Show Affiliations

Gladstone Institute of Neurological Disease, Department of Neurology, University of California, San Francisco, California, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15584903

Citation

Esposito, Luke, et al. "Intracellularly Generated Amyloid-beta Peptide Counteracts the Antiapoptotic Function of Its Precursor Protein and Primes Proapoptotic Pathways for Activation By Other Insults in Neuroblastoma Cells." Journal of Neurochemistry, vol. 91, no. 6, 2004, pp. 1260-74.
Esposito L, Gan L, Yu GQ, et al. Intracellularly generated amyloid-beta peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells. J Neurochem. 2004;91(6):1260-74.
Esposito, L., Gan, L., Yu, G. Q., Essrich, C., & Mucke, L. (2004). Intracellularly generated amyloid-beta peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells. Journal of Neurochemistry, 91(6), 1260-74.
Esposito L, et al. Intracellularly Generated Amyloid-beta Peptide Counteracts the Antiapoptotic Function of Its Precursor Protein and Primes Proapoptotic Pathways for Activation By Other Insults in Neuroblastoma Cells. J Neurochem. 2004;91(6):1260-74. PubMed PMID: 15584903.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intracellularly generated amyloid-beta peptide counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults in neuroblastoma cells. AU - Esposito,Luke, AU - Gan,Li, AU - Yu,Gui-Qiu, AU - Essrich,Christian, AU - Mucke,Lennart, PY - 2004/12/9/pubmed PY - 2005/1/22/medline PY - 2004/12/9/entrez SP - 1260 EP - 74 JF - Journal of neurochemistry JO - J Neurochem VL - 91 IS - 6 N2 - Most mutations in amyloid precursor proteins (APPs) linked to early onset familial Alzheimer's disease (FAD) increase the production of amyloid-beta peptides ending at residue 42 (Abeta42), which are released from APP by beta- and gamma-secretase cleavage. Stably transfected cells expressing wild-type human APP (APP(WT)) were more resistant to apoptosis-inducing treatments than cells expressing FAD-mutant human APP (APP(FAD)). Preventing Abeta42 production with an M596I mutation (beta-), which blocks beta-secretase cleavage of APP, or by treatment with a gamma-secretase inhibitor increased the resistance of APP(FAD)-expressing cells to apoptosis. Exposing hAPP(FAD/beta-) cells to exogenous Abeta42 or conditioned medium from Abeta42-producing APP(FAD) cells did not diminish their resistance to apoptosis. Preventing APP from entering the distal secretory pathway, where most Abeta peptides are generated, by retaining APP in the endoplasmic reticulum (ER)/intermediate compartment (IC) increased the resistance of APP(FAD)-expressing cells to apoptosis and did not alter the resistance of APP(WT)-expressing cells. p53-mediated gene transactivation after apoptosis-inducing treatments was much stronger in APP(FAD) cells than in hAPP(WT) or hAPP(FAD/beta-) cells. In contrast, upon induction of ER stress, cells expressing APP(FAD), hAPP(FAD/beta-), or APP(WT) had comparable levels of glucose-regulated protein-78 mRNA, an unfolded protein response indicator. We conclude that Abeta, especially intracellular Abeta, counteracts the antiapoptotic function of its precursor protein and predisposes cells to p53-mediated, and possibly other, proapoptotic pathways. SN - 0022-3042 UR - https://www.unboundmedicine.com/medline/citation/15584903/Intracellularly_generated_amyloid_beta_peptide_counteracts_the_antiapoptotic_function_of_its_precursor_protein_and_primes_proapoptotic_pathways_for_activation_by_other_insults_in_neuroblastoma_cells_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3042&date=2004&volume=91&issue=6&spage=1260 DB - PRIME DP - Unbound Medicine ER -