Sex-dependent worsening of NMDA-induced responses, anxiety, hypercortisolemia, and organometry of early peripheral immunoendocrine impairment in adult 3xTg-AD mice and their long-lasting ontogenic modulation by neonatal handling.

The neuroimmunomodulation hypothesis for Alzheimer's disease (AD) postulates that alterations in the innate immune system triggered by damage signals result in adverse effects on neuronal functions. The peripheral immune system and neuroimmunoendocrine communication are also impaired. Here we provide further evidence using a longitudinal design that also studied the long-lasting effects of an early life sensorial intervention (neonatal handling, from postnatal day 1-21) in 6-month-old (early stages of the disease) male and female 3xTg-AD mice compared to age- and sex-matched non-transgenic (NTg) mice with normal aging. The behavioral patterns elicited by the direct exposure to an open field, and the motor depression response evoked by NMDA (25 mg/kg, i.p) were found correlated to the organometry of peripheral immune-endocrine organs (thymus involution, splenomegaly, and adrenal glands' hypertrophy) and increased corticosterone levels, suggesting their potential value for diagnostic and biomonitoring.The NMDA-induced immediate and depressant motor activity and endocrine (corticosterone) responses were sensitive to sex and AD-genotype, suggesting worse endogenous susceptibility/neuroprotective response to glutamatergic excitotoxicity in males and in the AD-genotype. 3xTg-AD females showed a reduced immediate response, whereas the NTg showed higher responsiveness to subsequent NMDA-induced depressant effect than their male counterparts. The long-lasting ontogenic modulation by handling was shown as a potentiation of NMDA-depressant effect in NTg males and females, while sex × treatment effects were found in 3xTg-AD mice. Finally, NMDA-induced corticosterone showed sex, genotype and interaction effects with sexual dimorphism enhanced in the AD-genotype, suggesting different endogenous vulnerability/neuroprotective capacities and modulation of the neuroimmunoendocrine system.

Bizarre behaviors and risk assessment in 3xTg-AD mice at early stages of the disease.

Bizarre behaviors (stereotyped stretching, stereotyped rearing, backward movements and jumps) were conspicuously elicited in classical unconditioned tests with different levels of anxiogenic conditions. They were characterized for the first time as early-BPSD-like symptoms in 6 month-old male and female 3xTg-AD mice. The pattern of these behaviors differed from that exhibited by their age- and gender-matched NTg counterparts. Confrontation of an open and illuminated field was the best trigger of such behaviors as compared to mild neophobia in the corner test or the choice between two compartments in the dark-light box. Here we also report that increased freezing, delayed thigmotaxis and enhancement of emotional behaviors were early BPSD-like symptoms indicative of their response to low-stressful environments. Independently of the genotype, consistent gender effects pointed toward the relevance of female gender to study bizarre behaviors and risk assessment. The identification of items of behavior and its gender component were relevant to find out bidirectional and selective behavioral long-lasting effects of postnatal handling. This early life treatment reduced freezing and most of the bizarre behaviors whereas potentiated risk assessment and the horizontal locomotor activity. In contrast, vertical exploratory activity was not modified by the treatment. The results also talk in favor of the beneficence of early-life interventions on the behavioral outcome in adulthood in both healthy and disease conditions. As shown, the consideration of bizarre behaviors and risk assessment may become an additional tool for evaluating BPSD-like symptoms in relation to preventive and/or therapeutical strategies targeted at AD. It may also have a role in the evaluation of the potential risk factors for the disease.