Estrogen therapy fails to alter amyloid deposition in the PDAPP model of Alzheimer's disease.
Epidemiological studies implicate estrogen deprivation as a risk factor for Alzheimer's disease and postmenopausal estrogen replacement as protective factor. One potential mechanism involves estrogen attenuation of beta-amyloid (Abeta) peptide accumulation. We examined the effect of estrogen on amyloid accumulation in female PDAPP mice, which express human amyloid precursor protein (APP) with the V717F mutation. These animals deposit Abeta 1-42 in the hippocampus and neocortex and develop Alzheimer-like neuropathology. Mice were subjected to ovariectomy, ovariectomy with estrogen replacement, or sham surgery at 3 months of age, and levels of cerebral Abeta 1-40 and 1-42 were determined after 5 months of treatment. Neither estrogen deprivation nor estrogen replacement altered Abeta accumulation in the hippocampus or neocortex. Similarly, immunoreactivity for full-length human APP and secreted APPalpha was unchanged. Estrogen status of the animals was confirmed using a variety of techniques, including uterine and pituitary weight, vaginal cytology, and plasma estradiol concentrations. There was no correlation between plasma estradiol levels and accumulation of either Abeta 1-40 or Abeta 1-42 in the brain. Our observations indicate that long-term estrogen therapy does not alter amyloid pathology in PDAPP mice, an animal model of Alzheimer's disease, and question the role of estrogen in Abeta deposition in brain.
Green
Pattie S
PS
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA. psgreen@u.washington.edu
Bales
Kelly
K
Paul
Steven
S
Bu
Guojun
G
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004958:Estradiol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009154:Mutation; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D010446:Peptide Fragments / Q000378:metabolism; D012995:Solubility; D017211:Treatment Failure
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004958:Estradiol