The behavioural and neuropathologic sexual dimorphism and absence of MIP-3α in tau P301S mouse model of Alzheimer’s disease

Abstract

Background : Tau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer’s disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content. Method : We systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology and biomarkers in plasma and brain. Results : Male P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205 and astrocyte activation compared to that of wild type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris Water Maze and open field test. In addition, we characterized the absence of macrophage-inflammatory protein (MIP-3α) and the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 in the plasma of P301S transgenic mice, which can be served as potential plasma biomarkers in P301S Tg mice. Male P301S transgenic mice expressed more monokine induced by IFN-γ (MIG), tumor necrosis factor-α (TNF-α), IL-10 and IL-13 than those of female P301S mice. Conclusion : Our findings highlight sexual dimorphism in the behavior, neuropathology, and plasma proteins in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies, and the MIP-3α may be a new potential plasma biomarker.

Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau

“…This is consistent with a hyperactivity phenotype in 6-month-old PS19 mice, presenting with better, albeit not statistically significant, performance on the rotarod compared to WT control animals [ 28 ]. A related observation was reported recently in 3.5- to 12-month-old PS19 mice, showing a ~10% prolonged latency in the accelerating rotarod test [ 29 ].…”

“…Despite comparable loss of proximal pyramidal neurons with Tg4–42 hom at this time point, PS19/Tg4–42 hom displayed the worst performances in goal quadrant and platform parameters among the transgenic lines. The presence of spatial memory deficits in the PS19 line is controversial, with some studies pointing towards the development of deficits in the MWM test from a relatively young age of 5 [ 28 ] or 6.5 months [ 41 ], while others report initial deficits in spatial memory at 10 [ 42 ] or even 12 months of age [ 29 ], respectively. The tau transgenic line did not present with loss of CA1 pyramidal neurons at the considered time points, but neuron loss in the CA3 and reduced DG volume have been described in P301S mice starting at 8 months [ 26 , 43 ].…”

Sex differences in behaviour and molecular pathology in the 5XFAD model

“…Females presented with impairments only in specific behavioural tests, such as Morris water maze and open field and had lower expression of some inflammatory markers [10]. Conversely, no sex differences in gene expression were observed in other models such as our knock-in PLB1triple mice (with transgenes for APP, tau and PSEN1) or the PLB4 (knock-in of human BACE1 (β-secretase)) mice [11,12].…”

Reduction of the RNA Binding Protein TIA1 Exacerbates Neuroinflammation in Tauopathy

“…Thus, data from both male and female subjects were pooled for analyses at 5months. Since it has recently been demonstrated that pathology is present more consistently in P301S-PS19 males compared to females, particularly in advanced disease (Woerman et al, 2017;Sun et al, 2020) all male P301S subjects were studied in the 9-month cohort. Additionally, microglia are responsive to sex hormones (Kodama et al, 2020;review: Kodama and Gan, 2019).…”