Research ReportSex differences in β-amyloid accumulation in 3xTg-AD mice: Role of neonatal sex steroid hormone exposure
Research Highlights
►Female 3xTg-AD mice show accelerated Alzheimer-related pathology in comparison to male 3xTg-AD mice. ►Neonatally defeminized females exhibit a more male-like pattern of pathology. ►Neonatally demasculinized males exhibit a more female-like pattern of pathology. ►Sex differences in Alzheimer pathology involve organizational effects of sex steroid hormones.
Introduction
Women have a higher risk for the development of Alzheimer's disease (AD) than men. Epidemiological and observational studies have demonstrated a higher prevalence (Bachman et al., 1992, Jorm et al., 1987, Rocca et al., 1986) and incidence (Andersen et al., 1999, Fratiglioni et al., 2001, Jorm and Jolley, 1998, Ruitenberg et al., 2001) of AD in women. Further, AD appears to affect men and women differently, with women showing greater vulnerability to the disease. For example, at early stages of neurofibrillary tangle development, women exhibit greater senile plaque deposition than men (Corder et al., 2004). In addition, AD pathology is more strongly associated with clinical dementia in women than in men (Barnes et al., 2005).
Sex differences in AD may reflect differences between men and women in either of the two classic actions of sex steroid hormones: organizational effects during critical periods of development that induce permanent brain dimorphisms, or activational effects during adulthood that regulate adult brain function. Such activational effects of estrogens and testosterone are differentially diminished during aging in men and women. It is well established that estrogens have many beneficial effects in the brain, reviewed in (Wise, 2002) including numerous protective actions relevant to the prevention of AD, such as promotion of neuron viability and reduction of β-amyloid (Aβ) accumulation, reviewed in (Pike et al., 2009). The loss of neuroprotective estrogen actions as a consequence of estrogen depletion at menopause may increase the vulnerability of the female brain to AD and other disorders. Consistent with this theory, estrogen-based hormone therapy in postmenopausal women is associated with reduced risk of AD in some (Henderson et al., 1994, Kawas et al., 1997, Paganini-Hill and Henderson, 1996, Tang et al., 1996, Zandi et al., 2002) but not all studies (Espeland et al., 2004, Rapp et al., 2003). Similarly, ovariectomy-induced hormone depletion in wild-type rodents (Petanceska et al., 2000) and some transgenic mouse models of AD (Carroll et al., 2007, Levin-Allerhand et al., 2002, Zheng et al., 2002) can increase levels of the AD-related protein β-amyloid (Aβ), an effect attenuated by estradiol treatment. In men, age-related testosterone loss is linked with elevated levels of Aβ (Gillett et al., 2003, Rosario et al., 2009) and increased AD risk (Hogervorst et al., 2001, Moffat et al., 2004, Rosario et al., 2004, Rosario et al., 2009). In transgenic mouse models of AD, Aβ accumulation is accelerated under low testosterone conditions and reduced in the presence of high testosterone or dihydrotestosterone (McAllister et al., 2010, Rosario et al., 2006). Taken together, these studies suggest that adult exposure to estrogens and androgens may regulate the development of AD in women and men, respectively.
Another factor that may contribute to sex differences in AD risk is the organizational effects of sex steroid hormones during early development. Developmental patterns of estrogen and testosterone exposure induce numerous structural and functional differences between male and female brains (Cosgrove et al., 2007). Importantly, men and women also exhibit different vulnerabilities to several neurological disorders that occur prior to age-related hormone depletion, including post-traumatic stress disorder, schizophrenia, multiple sclerosis, autism, attention deficit disorder, and Tourette's syndrome (Cahill, 2006, Vagnerova et al., 2008). Thus, differences between male and female brains established during development may contribute to sex differences in vulnerability to disease, perhaps including AD.
The higher risk of AD in women may involve sex differences in the activational effects and/or organizational effects of estrogens and testosterone. To investigate these issues, we first compared the development of Aβ pathology in adult male and female triple transgenic (3xTg-AD) mice. Next, we assessed how the adult pattern of Aβ pathology is affected by disruption of the normal organizational effects of sex steroid hormones during critical developmental periods. Specifically, we defeminized neonatal female 3xTg-AD mice using transient testosterone treatment (Meek et al., 2006, Isgor and Sengelaub, 2003, Akhmadeev and Kalimullina, 2005) and demasculinized neonatal male 3xTg-AD mice by temporarily blocking testosterone action using the androgen receptor antagonist flutamide (Miyata et al., 2003, Houtsmuller et al., 1994, Meek et al., 2006, Kudwa et al., 2005). Alterations in adult pathology following these neonatal manipulations provide novel insight into the organizational role of sex steroid hormones on AD-related pathology.
Section snippets
Experiment 1: comparison of pathology development in male and female 3xTg-AD mice
To assess potential sex differences in AD-related pathology, Aβ accumulation and behavioral performance were compared in male and female 3xTg-AD mice across three age groups: 2–4 months, 6–8 months, and 12–14 months. The average age of males and females at each time point were not statistically different within age groups (average age in months ± standard error): female 2–4 months = 3.1 ± 0.0, male 2–4 months = 3.2 ± 0.1; (p = 0.78); female 6–8 months = 6.7 ± 0.3, male 6–8 months = 7.0 ± 0.4 (p = 0.37); female 12–14 months =
Discussion
In this study, we investigated sex differences in the progression of Aβ pathology in male and female 3xTg-AD mice and how this relationship is affected by alterations in sex steroid hormones during a critical neonatal period of neural development and sexual differentiation. Consistent with our previous findings (Carroll et al., 2007, Rosario et al., 2006), we observed that Aβ accumulation and deficits in hippocampal-dependent behavior increase with age in adult male and female 3xTg-AD mice.
Experimental design
Male and female 3xTg-AD mice harboring three human transgenes, APP(Swe), PS1(M146V) and tau(P301L) (Oddo et al., 2003), were maintained at the USC Gerontology vivarium on 12 h light on/off cycle and given ad libitum access to food and water. Mice were handled in accordance with the NIH Health and Wellness of Animal Subjects procedures and an institutionally approved IACUC protocol.
Acknowledgments
This research was funded by NIH grants AG23739 (CJP) and AG026572 (RD Brinton/CJP). JCC was supported by NIH grant F31NS059174. ERR was supported by NIH grant NS52143. The authors thank Dr. Elizabeth Adkins-Regan and Dr. Ruth Wood for their insightful comments.
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