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Estrogen Therapy Fails to Alter Amyloid Deposition in the PDAPP Model of Alzheimer’s Disease

Department of Pediatrics (P.S.G., G.B.), Washington University School of Medicine, St. Louis, Missouri 63110; Department of Medicine (P.S.G.), University of Washington, Seattle, Washington 98105; and Neuroscience Discovery Research (K.B., S.P.), Lilly Research Laboratories, Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Pattie S. Green, Division of Gerontology and Geriatric Medicine, Box 356426, University of Washington, Seattle, Washington 98195. Email: psgreen{at}u.washington.edu.

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 ß-amyloid (Aß) 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 Aß 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 Aß 1–40 and 1–42 were determined after 5 months of treatment. Neither estrogen deprivation nor estrogen replacement altered Aß accumulation in the hippocampus or neocortex. Similarly, immunoreactivity for full-length human APP and secreted APP 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 Aß 1–40 or Aß 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 Aß deposition in brain.

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