Rapamycin promotes beta-amyloid production via ADAM-10 inhibition.
Rapamycin is a well known immunosuppressant drug for rejection prevention in organ transplantation. Numerous clinical trials using rapamycin analogs, involving both children and adults with various disorders are currently ongoing worldwide. Most recently, rapamycin gained much attention for what appears to be life-span extending properties when administered to mice. The risk for Alzheimer disease (AD) is strongly and positively correlated with advancing age and is characterized by deposition of beta-amyloid peptides (Abeta) as senile plaques in the brain. We report that rapamycin (2.5muM), significantly increases Abeta generation in murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP). In concert with these observations, we found rapamycin significantly decreases the neuroprotective amino-terminal APP (amyloid precursor protein) cleavage product, soluble APP-alpha (sAPP-alpha) while increasing production of the beta-carboxyl-terminal fragment of APP (beta-CTF). These cleavage events are associated with decreased activation of a disintegrin and metallopeptidase domain-10 (ADAM-10), an important candidate alpha-secretase which opposes Abeta generation. To validate these findings in vivo, we intraperitoneal (i.p.) injected Tg2576 Abeta-overproducing transgenic mice with rapamycin (3mg/kg/day) for 2weeks. We found increased Abeta levels associated with decreased sAPP-alpha at an average rapamycin plasma concentration of 169.7+/-23.5ng/mL by high performance liquid chromatography (HPLC). These data suggest that although rapamycin may increase the lifespan in some mouse models, it may not decrease the risk for age-associated neurodegenerative disorders such as AD.
Zhang
Sheqing
S
Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, College of Medicine, University of South Florida, Tampa, FL 33613, USA.
Salemi
Jon
J
Hou
Hauyan
H
Zhu
Yuyan
Y
Mori
Takashi
T
Giunta
Brian
B
Obregon
Demian
D
Tan
Jun
J
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072197:ADAM10 Protein; D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008822:Mice, Transgenic; D020123:Sirolimus / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; D020123:Sirolimus