title: Neurochemical changes in a double transgenic mouse model of Alzheimer's disease fed a pro-oxidant diet.
abstract: Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing neurodegeneration and decreased monoamine neurotransmitters. We investigated the effect of administration of a pro-oxidant diet on the levels of monoamines and metabolites in the brains of wildtype and transgenic mice expressing mutant APP and PS-1 (TASTPM mice). Three-month-old TASTPM and wildtype (C57BL6/J) mice were fed either normal or pro-oxidant diet for 3 months. The neocortex, cerebellum, hippocampus and striatum were assayed for their monoamine and monoamine metabolite content using HPLC with electrochemical detection. Striatal tyrosine hydroxylase (TOH) levels were analysed by Western blotting. In the striatum, female TASTPM mice had higher levels of DOPAC and male TASTPM mice had higher levels of 5-HIAA compared to wildtype mice. Administration of pro-oxidant diet increased striatal MHPG, turnover of NA and 5-HT levels in female TASTPM mice compared to TASTPM mice fed control diet. The pro-oxidant diet also decreased DOPAC levels in female TASTPM mice compared to those fed control diet. Striatal TOH did not depend on diet, gender or genotype. In the neocortex, the TASTPM genotype increased levels of 5-HIAA in male mice fed control diet compared to wildtype mice. In the cerebellum, the TASTPM genotype led to decreased levels of HVA (male mice only) and also decreased turnover of DA (female mice only) compared to wildtype mice. These data suggest a sparing of monoaminergic neurones in the cortex, striatum and hippocampus of TASTPM mice fed pro-oxidant diet and could be indicative of increased activity in corticostriatal circuits. The decreased cerebellar levels of HVA and turnover of DA in TASTPM mice hint at possible axonal degeneration within this subregion.
authors.affiliation: Pharmidex Pharmaceutical Services Ltd., London, UK. E.Ash@Pharmidex.com
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ash
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Alavijeh
authors.forename: Alan M
authors.initials: AM
authors.lastname: Palmer
authors.forename: Cathy
authors.initials: C
authors.lastname: Mitchelmore
authors.forename: David R
authors.initials: DR
authors.lastname: Howlett
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.forename: Martin
authors.initials: M
authors.lastname: Broadstock
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018377:Neurotransmitter Agents / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D012015:Reference Standards; D019076:Transgenes; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D015306:Biogenic Monoamines; D018377:Neurotransmitter Agents; D016877:Oxidants; D053763:Presenilins; D014446:Tyrosine 3-Monooxygenase