Sex differences in β-amyloid accumulation in 3xTg-AD mice: Role of neonatal sex steroid hormone exposure

Abstract

The risk of Alzheimer's disease (AD) is higher in women than in men, a sex difference that likely results from the effects of sex steroid hormones. To investigate this relationship, we first compared progression of β-amyloid (Aβ) pathology in male and female triple transgenic (3xTg-AD) mice. We found that female 3xTg-AD mice exhibit significantly greater Aβ burden and larger behavioral deficits than age-matched males. Next, we evaluated how the organizational effects of sex steroid hormones during postnatal development may affect adult vulnerability to Aβ pathology. We observed that male 3xTg-AD mice demasculinized during early development exhibit significantly increased Aβ accumulation in adulthood. In contrast, female mice defeminized during early development exhibit a more male-like pattern of Aβ pathology in adulthood. Taken together, these results demonstrate significant sex differences in pathology in 3xTg-AD mice and suggest that these differences may be mediated by organizational actions of sex steroid hormones during development.

P4‐006: Sex‐specific Effects of a High Fat Diet on Indices of Metabolic Syndrome in 3xTgAD Mice: Implications for Alzheimer's Disease

“…Consistent with our previous findings [19], immunohistochemical Ab load was more severe in the subiculum of female compared to male 3xTg-AD mice maintained on standard diet (t = 22.2, p,0.05). Significantly increased immunoreactive Ab load was observed in both the hippocampus CA1 (F = 6.51, p,0.02; Figure 5A-E) and the subiculum (F = 5.04, p,0.05; Figure 5F-J) of high fat fed mice in both sexes.…”

“…We have reliably observed a strong correlation between Ab neuropathology and Y-maze SAB impairment in both male and female 3xTg-AD mice [19]. Mice were allowed to explore the Y-maze freely for 5 minutes or until 15 arm choices were made.…”

“…Every eighth section was pretreated with formic acid (99%) for 5 minutes, then immunolabeled with antibodies directed against Ab (#71-58000, 1:300 dilution, Zymed, CA, USA) or a phospho-specific epitope of tau (AT8, 1:1000 dilution, Peirce, IL, USA). Immunoreactivity was visualized using ABC Vector Elite and DAB kits (Vector Laboratories, CA, USA) as previously described [19].…”

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…However, the expression of genes that showed statistical significance (middle cluster) shows minimal intragroup variance (Figure 4a). The intragroup variability at the top and bottom clusters could be due to a less consistent pathology in male 3xTg‐AD mice (Carroll et al., 2010). To correlate the RNA changes at the protein level, western blot analysis demonstrated that the levels of multiple actin‐binding proteins (including drebrin, spinophilin, and p‐cortactin) were significantly reduced in the 3xTg‐AD mice (Figure 4c,d).…”

Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid β antibody fragment

“…Females were selected because they exhibit significantly greater Aβ burden and larger behavioral deficits than age-matched males. 14 We recently used this model to show that immunotherapy with an anti-Aβ antibody fragment is a potential tool for the treatment of AD. 15 Specifically, we constructed a single-chain variable fragment (scFv), scFv-h3D6, 16 from the humanized monoclonal antibody AAB-001 (mAb-h3D6, bapineuzumab).…”