Oxytocin attenuates microglial activation and restores social and non-social memory in APP/PS1 Alzheimer model mice.

Alzheimer's disease (AD) is characterized by neurodegeneration, memory loss, and social withdrawal. Brain inflammation has emerged as a key pathogenic mechanism in AD. We hypothesized that oxytocin, a pro-social hypothalamic neuropeptide with anti-inflammatory properties, could have therapeutic actions in AD. Here, we investigated oxytocin expression in experimental models of AD, and evaluated the therapeutic potential of treatment with oxytocin. Amyloid-ß peptide oligomers (AßOs) reduced oxytocin expression in vitro and in vivo, and treatment with oxytocin prevented microglial activation induced by AßOs in purified microglial cultures. Treatment of aged APP/PS1 mice, a mouse model of AD, with intranasal oxytocin attenuated microglial activation and favored deposition of Aß in dense core plaques, a potentially neuroprotective mechanism. Remarkably, treatment with oxytocin alleviated social and non-social memory impairments in aged APP/PS1 mice. Our findings point to oxytocin as a potential therapeutic target to reduce brain inflammation and correct memory deficits in AD.

A Specialized Nutritional Formulation Prevents Hippocampal Glial Activation and Memory Impairment Induced by Amyloid-ß Oligomers in Mice.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by progressive cognitive decline. Considerable evidence supports an important role of amyloid-ß oligomers (AßOs) in the pathogenesis of AD, including the induction of aberrant glial activation and memory impairment. OBJECTIVE: We have investigated the protective actions of a nutritional formulation, denoted AZ formulation, on glial activation and memory deficits induced by intracerebroventricular (i.c.v.) infusion of AßOs in mice. METHODS: Two-month-old male mice were treated orally with AZ formulation or isocaloric placebo for 30 consecutive days. Microglial and astrocytic activation were analyzed by immunohistochemistry in the hippocampus 10 days after i.c.v. infusion of AßOs (n = 5 mice per experimental condition). Memory loss was assessed by the novel object recognition (NOR) test (n = 6-10 mice per experimental condition). RESULTS: Oral treatment with the AZ formulation prevented hippocampal microglial and astrocytic activation induced by i.c.v. infusion of AßOs. The AZ formulation further protected mice from AßO-induced memory impairment. CONCLUSION: Results suggest that administration of the AZ formulation may comprise a promising preventative and non-pharmacological strategy to reduce brain inflammation and attenuate memory impairment in AD.

Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation.

BACKGROUND: Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation. METHODS: Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests. RESULTS: Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1ß and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation. CONCLUSIONS: Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age-related cognitive impairments.