Augmented senile plaque load in aged female beta-amyloid precursor protein-transgenic mice.

Transgenic mice (Tg2576) overexpressing human beta-amyloid precursor protein with the Swedish mutation (APP695SWE) develop Alzheimer's disease-like amyloid beta protein (Abeta) deposits by 8 to 10 months of age. These mice show elevated levels of Abeta40 and Abeta42, as well as an age-related increase in diffuse and compact senile plaques in the brain. Senile plaque load was quantitated in the hippocampus and neocortex of 8- to 19-month-old male and female Tg2576 mice. In all mice, plaque burden increased markedly after the age of 12 months. At 15 and 19 months of age, senile plaque load was significantly greater in females than in males; in 91 mice studied at 15 months of age, the area occupied by plaques in female Tg2576 mice was nearly three times that of males. By enzyme-linked immunosorbent assay, female mice also had more Abeta40 and Abeta42 in the brain than did males, although this difference was less pronounced than the difference in histological plaque load. These data show that senescent female Tg2576 mice deposit more amyloid in the brain than do male mice, and may provide an animal model in which the influence of sex differences on cerebral amyloid pathology can be evaluated.

[1]  S. Gandy,et al.  Ovariectomy and 17β-estradiol modulate the levels of Alzheimer’s amyloid β peptides in brain , 2000, Neurology.

[2]  K. Duff,et al.  Behavioral Changes in Transgenic Mice Expressing Both Amyloid Precursor Protein and Presenilin-1 Mutations: Lack of Association with Amyloid Deposits , 1999, Behavior genetics.

[3]  H Morgenstern,et al.  Development of dementing illnesses in an 80‐year‐old volunteer cohort , 1989, Annals of neurology.

[4]  H. J. G. Gundersen,et al.  The new stereological tools: Disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[5]  Anthony Gamst,et al.  Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer Disease: A Randomized Controlled Trial , 2000 .

[6]  P. Greengard,et al.  Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. , 1994, The Journal of biological chemistry.

[7]  P. Greengard,et al.  Estrogen reduces neuronal generation of Alzheimer β-amyloid peptides , 1998, Nature Medicine.

[8]  M. Walker.  Menopause in female rhesus monkeys , 1995, American journal of primatology.

[9]  H C Liu,et al.  Effects of estrogen on cognition, mood, and cerebral blood flow in AD , 2000, Neurology.

[10]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[11]  P. Mölsä,et al.  Epidemiology of dementia in a Finnish population , 1982, Acta neurologica Scandinavica.

[12]  Ulrich Mohr,et al.  Pathobiology of the aging mouse , 1996 .

[13]  Yaakov Stern,et al.  Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease , 1996, The Lancet.

[14]  B. Winblad,et al.  A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N–terminus of β–amyloid , 1992, Nature Genetics.

[15]  D. Price,et al.  Mutant genes in familial Alzheimer's disease and transgenic models. , 1998, Annual review of neuroscience.

[16]  M. Mattson,et al.  Estrogens Attenuate and Corticosterone Exacerbates Excitotoxicity, Oxidative Injury, and Amyloid β‐Peptide Toxicity in Hippocampal Neurons , 1996, Journal of neurochemistry.

[17]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[18]  S. Korenman,et al.  The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. , 1976, The Journal of clinical endocrinology and metabolism.

[19]  H. Wiśniewski,et al.  Increased plasma amyloid β protein 1–42 levels in Down syndrome , 1998, Neuroscience Letters.

[20]  F. Sohrabji,et al.  Presumptive Estrogen Target Neurons Express mRNAs for both the Neurotrophins and Neurotrophin Receptors: A Basis for Potential Developmental Interactions of Estrogen with the Neurotrophins , 1993, Molecular and Cellular Neuroscience.

[21]  John Hardy,et al.  Amyloid, the presenilins and Alzheimer's disease , 1997, Trends in Neurosciences.

[22]  B. Sommer,et al.  Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[23]  A. Korten,et al.  The prevalence of dementia: A quantitative integration of the literature , 1987, Acta psychiatrica Scandinavica.

[24]  M. Seeman.  Psychopathology in women and men: focus on female hormones. , 1997, The American journal of psychiatry.

[25]  W. Hazzard,et al.  Lipoprotein, apolipoprotein, and lipolytic enzyme changes following estrogen administration in postmenopausal women. , 1989, Journal of lipid research.

[26]  E. Niki,et al.  [34] Estrogens as antioxidants , 1990 .

[27]  M. Sano.  Understanding the role of estrogen on cognition and dementia. , 2000, Journal of neural transmission. Supplementum.

[28]  H J Gundersen,et al.  The efficiency of systematic sampling in stereology and its prediction * , 1987, Journal of microscopy.

[29]  B. Winblad,et al.  Very Old Women at Highest Risk of Dementia and Alzheimer's Disease , 1997, Neurology.