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Editorial: Dysmetabolism, obesity, and inflammation: Three prominent actors in the drama of major neuropsychiatric disorders
Full text linkThe role of endocannabinoid signaling in the molecular mechanisms of neurodegeneration in Alzheimer's disease
Full text linkAlzheimer's disease (AD) is the most common form of progressive neurodegenerative disease characterized by cognitive impairment and mental disorders. The actual cause and cascade of events in the progression of this pathology is not fully determined. AD is multifaceted in nature and is linked to different multiple mechanisms in the brain. This aspect is related to the lack of efficacious therapies that could slow down or hinder the disease onset/progression. The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway. Recently, the endocannabinoid system emerged as a novel potential therapeutic target to treat AD. In fact, exogenous and endogenous cannabinoids seem to be able to modulate multiple processes in AD, although the mechanisms that are involved are not fully elucidated. This review provides an update of this area. In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets
From obesity resistance to obesity prediction and prevention?
Full text linkComment on:
Regulation of hypothalamic neuropeptides gene expression in diet induced obesity resistant rats: possible targets for obesity prediction? [Front Neurosci. 2015
Astrocytic palmitoylethanolamide pre-exposure exerts neuroprotective effects in astrocyte-neuron co-cultures from a triple transgenic mouse model of Alzheimer's disease
No full textPalmitoylethanolamide (PEA) is an endogenous lipid mediator that, also by blunting astrocyte activation, demonstrated beneficial properties in several in vitro and in vivo models of Alzheimer's disease (AD). In the present study, we used astrocyte-neuron co-cultures from 3xTg-AD mouse (i.e. an animal model of AD) cerebral cortex to further investigate on the role of astrocytes in PEA-induced neuroprotection. To this aim, we evaluated the number of viable cells, apoptotic nuclei, microtubule-associated protein-2 (MAP2) positive cells and morphological parameters in cortical neurons co-cultured with cortical astrocytes pre-exposed, or not, to Aβ42 (0.5 μM; 24 h) or PEA (0.1 μM; 24 h). Pre-exposure of astrocytes to Aβ42 failed to affect the viability, the number of neuronal apoptotic nuclei, MAP2 positive cell number, neuritic aggregations/100 μm, dendritic branches per neuron, the neuron body area, the length of the longest dendrite and number of neurites/neuron in 3xTg-AD mouse astrocyte-neuron co-cultures. Compared to neurons from wild-type (non-Tg) mouse co-cultures, 3xTg-AD mouse neurons co-cultured with astrocytes from this mutant mice displayed higher number of apoptotic nuclei, lower MAP2 immunoreactivity and several morphological changes. These signs of neuronal suffering were significantly counteracted when the 3xTg-AD mouse cortical neurons were co-cultured with 3xTg-AD mouse astrocytes pre-exposed to PEA. The present data suggest that in astrocyte-neuron co-cultures from 3xTg-AD mice, astrocytes contribute to neuronal damage and PEA, by possibly counteracting reactive astrogliosis, improved neuronal survival. These findings further support the role of PEA as a possible new therapeutic opportunity in AD treatment
Use of mammalian target of rapamycin inhibitor for treating pathologies including neurodegenerative diseases (Alzheimer's disease), neuroinflammatory diseases and tumor diseases with neurological involvement, by intrathecal administration
No full textThe invention relates to the use of inhibitors of the enzyme mTOR kinase (mammalian target of rapamycin) in the treatment of neuro-oncologic diseases, in particular tuberous sclerosis, neurodegenerative diseases, in particular Alzheimer's disease, and neuroinflammatory diseases, in particular multiple sclerosis and primary progressive aphasia, via intrathecal, or preferably intraventricular, administration of said inhibitors
Effects of intrathecal administration of everolimus in a triple transgenic mouse model of Alzheimer's disease
No full textOverwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signaling in the pathogenesis of Alzheimer's disease (AD). To investigate the relation between Aβ and mTOR, we injected the synthetic analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent amyloid-β peptide (Aβ) and tau accumulation associated with cognitive decline. In particular, 6-month-old 3×Tg-AD mice and age-matched wild-type littermates (Non-Tg) were used. At this age, the 3×Tg-AD mice show early intraneuronal Aβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline. The mTOR enzymatic activity and the levels of phosphorylated p70S6K, a downstream target of mTOR, was significantly increased in the 3×Tg-AD mice compared to control mice; centrally administered everolimus significantly reduced the phosphorylation of p70S6K and decreased the levels of APP and Aβ. The Aβ reduction was confirmed by immunohistochemical analysis. We next sought to investigate the effect of everolimus on the learning and memory of 3×Tg-AD mice, using three independent behavioral paradigms: the novel object recognition test, a behavioral task mainly dependent on multiple cortical areas, the inhibitory avoidance, which is highly dependent on the hippocampus and amygdala, and the spatial version of the Morris water maze, a hippocampal-dependent task. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits in the 3×Tg-AD mice. In conclusion, we show that autophagy induction via everolimus may represent a valid therapeutic strategy in AD when administered early in the disease progression
Glutamate and mitochondria: two prominent players in the oxidative stress-induced neurodegeneration
Full text linkThe aetiology of major neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) is still unknown, but increasing evidences suggest that glutamate and mitochondria are two prominent players in the oxidative stress (OS) process that underlie these illnesses. Although AD and PD have distinct pathological and clinical features, OS is a common mechanism contributing to neuronal damage. Glutamate is an important neurotransmitter in neurons and glial cells and is strongly dependent on calcium homeostasis and on mitochondrial function. In the present work we focused on glutamate- induced calcium signaling and its relation to the mitochondrial dysfunction with cell death processes. In addition, we have discussed how alterations in this pathway may lead or aggravate the neurodegenerative diseases. Finally, this review aims to stimulate further studies on this issue and thereby engage a new perspective regarding the design of possible therapeutic agents or the identification of biomarkers
Antinutritional effects of fumonisin B1 and pathophysiological consequences
Full text linkDue to its structural similarity with sphingosine, fumonisin B(1) (FB(1)) inhibits ceramide synthase (a key enzyme of sphingolipid biosynthesis) leading to an intracellular accumulation of sphingoid bases with a consequent increase of sphinganine/sphingosine (SA/SO) ratio. In adult male rats, dietary exposure to fumonisin induces a significant increase in both SA concentrations and SA/SO ratio in kidney, but not in liver and brain, as well as a significant reduction of body weight gain. Regarding the brain, the developing rat is more sensitive to FB(1) than the adult rat. FB(1) treatment produces in the forebrain and brainstem: (i) an increase in SA levels and SA/SO ratio, (ii) a reduction in myelin deposition, and (iii) an impairment of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activity. FB(1) effects on myelin are similar to those produced by starvation (temporary removal of pups from dam during postnatal period), thus suggesting that hypomyelination could be due, at least partly, to a nutritional deficiency. Finally, FB(1) reduces the uptake of folate in different cell lines. The resulting folate deficiency could explain the association of FB(1) exposure with neural tube defects
Everolimus rescues the early learning and memory deficits and ameliorates the AD-like pathology in the 3xTg-AD mice
No full textOverwhelming evidence shows a primary role for the mammalian target of rapamycin (mTOR) signaling in the pathogenesis of Alzheimer’s disease (AD). To investigate the relation between Aβ and mTOR, we injected the synthetic analogue of rapamycin, everolimus, into the cerebroventricular space of a triple transgenic mouse model of AD (3×Tg-AD), which develops age-dependent amyloid-β peptide (Aβ) and tau accumulation associated with cognitive decline. In particular, 6-month-old 3×Tg-AD mice and age-matched wild-type littermates (Non-Tg) were used. At this age, the 3×Tg-AD mice show early intraneuronal Aβ accumulation and tau mislocalization, which correlate with the onset of cognitive decline. The mTOR enzymatic activity and the levels of phosphorylated p70S6K, a downstream target of mTOR, was significantly increased in the 3×Tg-AD mice compared to control mice; centrally administered everolimus significantly reduced the phosphorylation of p70S6K and decreased the levels of APP and Aβ. The Aβ reduction was confirmed by immunohistochemical analysis. We next sought to investigate the effect of everolimus on the learning and memory of 3×Tg-AD mice, using three independent behavioral paradigms: the novel object recognition test, a behavioral task mainly dependent on multiple cortical areas, the inhibitory avoidance, which is highly dependent on the hippocampus and amygdala, and the spatial version of the Morris water maze, a hippocampal-dependent task. Overall, our data indicate that everolimus infusion rescued the early learning and memory deficits in the 3×Tg-AD mice. In conclusion, we show that autophagy induction via everolimus may represent a valid therapeutic strategy in AD when administered early in the disease progression
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