Induction of Alzheimer's-like changes in brain of mice expressing mutant APP fed excess methionine.
Elevated plasma homocysteine, a risk factor for Alzheimer's disease, could result from increased production from methionine or by inefficient clearance by folate- and B-vitamin-dependent pathways. Understanding the relative contributions of these processes to pathogenesis is important for therapeutic strategies designed to lower homocysteine. To assess these alternatives, we elevated plasma homocysteine by feeding mutant amyloid precursor protein (APP)-expressing mice diets with either high methionine (HM) or deficient in B-vitamins and folate (B Def). Mutant APP mice fed HM demonstrated increased brain beta amyloid. Interestingly, this increase was not observed in mutant APP mice fed B Def diet, nor was it observed in C57Bl6 or YAC-APP mice fed HM. Furthermore, HM, but not B Def, produced a prolonged increase in brain homocysteine only in mutant APP mice but not wild-type mice. These changes were time-dependent over 10 weeks. Further, by 10 weeks HM increased brain cholesterol and phosphorylated tau in mutant APP mice. Transcriptional profiling experiments revealed robust differences in RNA expression between C57Bl6 and mutant APP mice. The HM diet in C57Bl6 mice transiently induced a transcriptional profile similar to mutant APP cortex, peaking at 2 weeks , following a time course comparable to brain homocysteine changes. Together, these data suggest a link between APP and methionine metabolism.
Department of Neurology, Merck Research Laboratory, West Point, Pennsylvania, USA. alexander_mccampbell@merck.com
Alexander
A
McCampbell
Keith
K
Wessner
Michael W
MW
Marlatt
Carrie
C
Wolffe
Dawn
D
Toolan
Alexei
A
Podtelezhnikov
Suzie
S
Yeh
Rena
R
Zhang
Peter
P
Szczerba
Keith Q
KQ
Tanis
John
J
Majercak
William J
WJ
Ray
Mary
M
Savage
D000544:Alzheimer Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D014804:Vitamin B Deficiency / Q000235:genetics / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D008715:Methionine