%0 Journal Article
%T A Novel Mouse Model of Alzheimer's Disease with Chronic Estrogen Deficiency Leads to Glial Cell Activation and Hypertrophy
%A Annik Prat
%A Maik Behrendt
%A Edwige Marcinkiewicz
%A Sebastien Boridy
%A Ram M. Sairam
%A Nabil G. Seidah
%A Dusica Maysinger
%J Journal of Aging Research
%D 2011
%I Hindawi Publishing Corporation
%R 10.4061/2011/251517
%X The role of estrogens in Alzheimer's disease (AD) involving ¦Â-amyloid (A¦Â) generation and plaque formation was mostly tested in ovariectomized mice with or without APP mutations. The aim of the present study was to explore the abnormalities of neural cells in a novel mouse model of AD with chronic estrogen deficiency. These chimeric mice exhibit a total FSH-R knockout (FORKO) and carry two transgenes, one expressing the ¦Â-amyloid precursor protein (APPsw, Swedish mutation) and the other expressing presenilin-1 lacking exon 9 (PS1¦¤9). The most prominent changes in the cerebral cortex and hippocampus of these hypoestrogenic mice were marked hypertrophy of both cortical neurons and astrocytes and an increased number of activated microglia. There were no significant differences in the number of A¦Â plaques although they appeared less compacted and larger than those in APPsw/PS1¦¤9 control mice. Similar glia abnormalities were obtained in wild-type primary cortical neural cultures treated with letrozole, an aromatase inhibitor. The concordance of results from APPsw/PS1¦¤9 mice with or without FSH-R deletion and those with letrozole treatment in vitro (with and without A¦Â treatment) of primary cortical/hippocampal cultures suggests the usefulness of these models to explore molecular mechanisms involved in microglia and astrocyte activation in hypoestrogenic states in the central nervous system. 1. Introduction In the brain, estradiol is formed in neurons and a subpopulation of astrocytes by aromatase-mediated conversion of precursor androgens [1]. Estrogen deficiency was reported to accelerate ¦Â-amyloid (A¦Â) plaque formation in an Alzheimer¡¯s disease (AD) mouse model combining an aromatase deficiency and an APP23 transgene [2]. There was no significant difference between the estrogen levels in APP23 and wild-type mice independent of age (3, 6, and 12 months); however, the estrogen levels in the brains of APP23-aromatase knockout mice were significantly reduced compared to age-matched ovariectomized APP23 mice. Furthermore, microglial cultures prepared from the brains of these APP23 mice showed impaired A¦Â clearance and/or degradation [2]. Another model of estrogen imbalance was provided by follicule-stimulating hormone receptor (FSHR) knockout (FORKO) mice [3]. Our earlier studies showed that homozygous females were infertile, whereas males exhibited reduced fertility [4]. Similarly, inactivating mutations in the FSHR gene in women cause absolute infertility and amenorrhea [5]. Young and aged FORKO mice exhibit several biochemical and morphological abnormalities
%U http://www.hindawi.com/journals/jar/2011/251517/