The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of theirCNSdue to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age‐related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration inTSmice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed inTSmice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition inTSmice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampalLTPin trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus ofTSmice. These results indicate that the cognitive‐enhancing effects of melatonin in adultTSmice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression ofDSneuropathology.

Previous studies have demonstrated that melatonin administration improves spatial learning and memory and hippocampal long-term potentiation in the adult Ts65Dn (TS) mouse, a model of Down syndrome (DS). This functional benefit of melatonin was accompanied by protection from cholinergic neurodegeneration and the attenuation of several hippocampal neuromorphological alterations in TS mice. Because oxidative stress contributes to the progression of cognitive deficits and neurodegeneration in DS, this study evaluates the antioxidant effects of melatonin in the brains of TS mice. Melatonin was administered to TS and control mice from 6 to 12 months of age and its effects on the oxidative state and levels of cellular senescence were evaluated. Melatonin treatment induced antioxidant and antiaging effects in the hippocampus of adult TS mice. Although melatonin administration did not regulate the activities of the main antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase) in the cortex or hippocampus, melatonin decreased protein and lipid oxidative damage by reducing the thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PC) levels in the TS hippocampus due to its ability to act as a free radical scavenger. Consistent with this reduction in oxidative stress, melatonin also decreased hippocampal senescence in TS animals by normalizing the density of senescence-associated β-galactosidase positive cells in the hippocampus. These results showed that this treatment attenuated the oxidative damage and cellular senescence in the brain of TS mice and support the use of melatonin as a potential therapeutic agent for age-related cognitive deficits and neurodegeneration in adults with DS.

There is currently no effective pharmacological therapy to improve the cognitive dysfunction of individuals with Down syndrome (DS). Due to the overexpression of several chromosome 21 genes, cellular and systemic oxidative stress (OS) is one of the most important neuropathological processes that contributes to the cognitive deficits and multiple neuronal alterations in DS. In this condition, OS is an early event that negatively affects brain development, which is also aggravated in later life stages, contributing to neurodegeneration, accelerated aging, and the development of Alzheimer’s disease neuropathology. Thus, therapeutic interventions that reduce OS have been proposed as a promising strategy to avoid neurodegeneration and to improve cognition in DS patients. Several antioxidant molecules have been proven to be effective in preclinical studies; however, clinical trials have failed to show evidence of the efficacy of different antioxidants to improve cognitive deficits in individuals with DS. In this review we summarize preclinical studies of cell cultures and mouse models, as well as clinical studies in which the effect of therapies which reduce oxidative stress and mitochondrial alterations on the cognitive dysfunction associated with DS have been assessed.

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.