Regular articleGender differences in the amount and deposition of amyloidβ in APPswe and PS1 double transgenic mice
Introduction
Alzheimer's disease (AD) is the most common cause of dementia in the elderly, with the neuropathological hallmarks of amyloid plaques, tangles, and a progressive loss of neurons in the neocortex Evans et al., 1989, Braak and Braak, 1991. At the earliest stage of AD, pathology is largely restricted to the medial temporal lobe; in later stages it spreads to the associative temporal and parietal cortical areas and, finally, to all cortical areas Hyman et al., 1984, Braak and Braak, 1991. Epidemiological studies have shown higher prevalence rates of AD in women Molsa et al., 1982, Jorm et al., 1987, Hagnell et al., 1992, Letenneur et al., 1994, Brayne et al., 1995, Fratiglioni et al., 1997, Fratiglioni et al., 2000, Andersen et al., 1999, but the physiological basis that underlies this sex difference in the prevalence of AD is still elusive. It has been suggested that after menopause, a declining estrogenic stimulus, either from dramatically reduced levels of circulating estrogen or from aromatizable androgen levels, both of ovarian origin, might make estrogen target neurons in the brain more susceptible to age- or disease-related processes. This idea is supported by a study that showed lower serum estrogen values in women with AD than in age-matched controls (Honjo et al., 1989). Clinical trials with estrogen supplementation have suggested that the onset of AD is delayed and that the risk of AD is reduced in the women who receive estrogen Honjo et al., 1989, Tang et al., 1996, Henderson et al., 2000. However, some more recent studies have suggested that estrogen supplementation is not beneficial for Alzheimer's disease, especially in patients with established AD Cholerton et al., 2002, Fillit, 2002.
Understanding the disease mechanisms of AD has been facilitated by the discovery of the genetic mutations that underlie inherited forms of early onset AD. Several mutations in the genes encoding the amyloid precursor protein (APP), presenilin-1 (PS-1), and PS-2 proteins have been shown to lead to familial AD Price et al., 1995, Hardy, 1997. These mutations lead to the overproduction of amyloidβ (Aβ) which is followed by the extracellular deposition of Aβ in the brain Price et al., 1995, Hardy, 1997. At present several transgenic mouse models of AD (that carry APP and/or PS1 genes with mutations) are used and most of these models develop progressive, age-related Aβ neuropathology with amyloid plaques and elevated levels of Aβ Games et al., 1995, Hsiao et al., 1996, Borchelt et al., 1997. Our transgenic mice have elevated levels of the highly fibrillogenic Aβ42 peptide and develope amyloid plaques around the age of 9 months; the amyloid plaques are first present in the subiculum and caudal cortex (Liu et al., 2002a), and later the amyloid plaques are present in nearly all cortical areas (Borchelt et al., 1997).
We have noted that female mice have higher levels of Aβ and pathology than age-matched males (Van Groen et al., 2000). Recently this has also been shown in another aging AD model mouse (the Tg2576 mouse) (Callahan et al., 2001).
In the present study, we have used transgenic mice expressing both the human APP695swe and the PS1-A246E mutation (Borchelt et al., 1997) to investigate more closely the gender difference in Aβ levels and amyloid burden between female and male mice and the development of this relationship with age.
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Animals
Transgenic mice expressing either the human PS1 (A246E mutation) or a chimeric mouse/human APP695 (K595N, M596L, Swedish mutation; APPswe) (Borchelt et al., 1997) were back-crossed to C57BL/6J mice for six generations, and then the lines were crossed together to generate double transgenic mice, i.e., expressing both transgenes. Male and female double transgenic mice were used in this study. The housing conditions were controlled (temperature, 21 ± 1°C; light from 7:00 to 19:00; humidity
Aβ levels, age
In male mice from the age of 4 to 12 months there was a significant increase in the level of Aβ40 (Table 1; Fig. 1, Fig. 2 ), but from the age of 12 to 17 months there was a nonsignificant increase in the level of Aβ40 (Table 1; Fig. 1, Fig. 2). On the other hand, the level of Aβ42 increased significantly from 4 to 12 and from 12 to 17 months (Table 1; Fig. 1, Fig. 2). In the female mice, however, there was a significant increase in both the Aβ40 (Table 1; Fig. 1, Fig. 2) and the Aβ42 (Table 1
Discussion
Our data show that gender plays an important role in the pathogenesis of AD, i.e., sex-related differences are present in Aβ levels and in amyloid deposits in the hippocampus in our AD model mice. First, the Aβ40 level and the Aβ42 level are significantly increased in female mice compared to male mice, at all ages measured (i.e., at 4, 12, and 17 months of age). Second, at both 12 and 17 months of age the amyloid burden is substantially higher in female mice compared to male mice (at 4 months
Acknowledgements
This work was supported by the Academy of Finland (Grant 46000) and EVO-Grant (Grant 5510) of Kuopio University Hospital. We thank Dr. David Borchelt (Johns Hopkins University, Baltimore, MD, USA) for providing the APP and PS1 mouse lines and Dr. Tobias Hartmann (Heidelberg University, Germany) for providing the W0-2 antibody for the study. The authors also thank Pasi Miettinen and Päivi Räsänen for their skillful technical assistance.
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