Gender-Specific Neuroimmunoendocrine Aging in a Triple-Transgenic 3×Tg-AD Mouse Model for Alzheimer’s Disease and Its Relation with Longevity

Abstract

In the present work, we briefly review the evidence on the key role played by the neuroimmunoendocrine network in the etiopathogenesis of Alzheimer’s disease (AD) and provide new behavioral, immune and endocrinological data obtained on old male and female triple-transgenic 3×Tg-AD mice harboring PS1_M146V, APP_Swe and tau_P301L transgenes in contrast to wild-type animals. The results indicate that several aspects of the impairment of the neuroimmunoendocrine network that occurs with aging are more evident in the 3×Tg-AD mice, especially in males. This supports the hypothesis of a premature immunosenescence as a pathogenically relevant factor in AD which was found to be enhanced in the 3×Tg-AD males, suggesting that this could also be responsible for the increased morbidity and mortality of these subjects. Therefore, future research on strategies that could improve the immune system and the other regulatory systems, such as the nervous and the endocrine system, as well as their communication, could have preventive and/or therapeutical effects on that disease. The results also show the relevance of gender differences that should be taken into consideration in both basic and clinical research for assessing new strategies for the control of AD.

Age-dependent regulation of obesity and Alzheimer-related outcomes by hormone therapy in female 3xTg-AD mice

“…In rodents, estradiol treatment [94], particularly when delivered chronically [95, 96], is associated with development of urinary tract infections including pyometra. Further, 3xTg-AD mice exhibit accelerated immunosenescence [97] and mortality [26], which may have interacted with HT to yield poor health outcomes in aging female 3xTg-AD mice. Second, we did not consider potential differences in circulating estradiol levels associated with adiposity, which was increased by both aging and HFD.…”

Gender-Specific Neuroimmunoendocrine Response to Treadmill Exercise in 3xTg-AD Mice

“…Tissue samples were stored at −80°C for further biochemical analysis (see below). The size (weight in mg) and relative size (% versus body weight) of the thymus were recorded as an indirect measure of the putative impairment (involution) of the peripheral immunological system [24]. …”

“…Their associated behavioral disturbances include cognitive and noncognitive symptoms (i.e., Behavioral and psychological symptoms of dementia, BPSD) and other neuronal symptoms that mimic AD dementia [22]. In addition, these mice present a gender-related progression of AD changes [23, 24]. Therefore, 3xTg-AD is a valuable model for preclinical intervention studies.…”

Obesity and sex interact in the regulation of Alzheimer's disease

“…In support of this idea, the association between inflammatory cytokines and decreased brain volume is reportedly stronger in men (Jefferson et al, 2007). In an AD transgenic mouse model, the immune system is more impaired in male versus female mice (Giménez-Llort et al, 2008). Overall, findings point to increased inflammation in response to obesity in females, as well as a greater association between inflammation and cognitive decline in women.…”