Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis.
Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of beta-amyloid (Abeta). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Abeta can be toxic, the alpha-secretase cleaved APP (sAPPalpha) is neuroprotective. However, the mechanism of sAPPalpha protection is unknown. Here, we show that sAPPalpha increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Abeta-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPalpha-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Abeta-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPalpha and transthyretin and do not develop the tau phosphorylation or neuronal loss characteristic of human AD. Chronic infusion of an antibody against transthyretin into the hippocampus of mice overexpressing APP with the Swedish mutation (APP(Sw)) leads to increased Abeta, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPalpha and protects APP(Sw) mice from developing many of the neuropathologies observed in AD.
Stein
Thor D
TD
Neuroscience Training Program, University of Wisconsin, Madison, Wisconsin 53705-2222, USA.
Anders
Nicholas J
NJ
DeCarli
Charles
C
Chan
Sic L
SL
Mattson
Mark P
MP
Johnson
Jeffrey A
JA
D000375:Aging; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases; D002352:Carrier Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation; D018621:PrPC Proteins / Q000235:genetics; D011228:Prealbumin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D058255:Protease Nexins; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D019076:Transgenes; D051025:bcl-Associated Death Protein; D016875:tau Proteins / Q000378:metabolism
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D018621:PrPC Proteins; D011228:Prealbumin; D058255:Protease Nexins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C075222:amyloid beta-protein (1-42); D051025:bcl-Associated Death Protein; D016875:tau Proteins; D007335:Insulin-Like Growth Factor II; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse