Brainiac Caspases: Beyond the Wall of Apoptosis.

For the last two decades, caspases, a family of cysteine-aspartic proteases, have evolved from being considered solely as regulators of apoptosis or inflammation to having a wider range of functions. In this mini review, we focus on the most recent "non-apoptotic" roles of caspases in the CNS, particularly in neurons, astrocytes and oligodendrocytes. Non-apoptotic caspase functions in microglia have already been reviewed extensively elsewhere. Here we discuss the involvement of caspases in the activation of the inflammasome, autophagy, and non-apoptotic forms of cell death such as necroptosis and pyroptosis. Also, we review the involvement of caspases in synapses and the processing of aggregates key to neurodegenerative diseases such as Parkinson's, Alzheimer's and Huntington's diseases. Likewise, we mention the recently described involvement of caspases in mitochondrial biogenesis, which is a function independent of the enzymatic activity. We conclude discussing the relevance that "new" functions of caspases have in the CNS and the future of this field of research.

TET2 Regulates the Neuroinflammatory Response in Microglia.

Epigenomic mechanisms regulate distinct aspects of the inflammatory response in immune cells. Despite the central role for microglia in neuroinflammation and neurodegeneration, little is known about their epigenomic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-κB-dependent pathway. We found that TET2 regulates early gene transcriptional changes, leading to early metabolic alterations, as well as a later inflammatory response independently of its enzymatic activity. We further show that TET2 regulates the proinflammatory response in microglia of mice intraperitoneally injected with LPS. We observed that microglia associated with amyloid ß plaques expressed TET2 in brain tissue from individuals with Alzheimer's disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

Hydroxytyrosol protects from aging process via AMPK and autophagy; a review of its effects on cancer, metabolic syndrome, osteoporosis, immune-mediated and neurodegenerative diseases.

Aging is a complex process. It is considered a risk factor for several diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and diabetes, most of which have an oxidative and inflammatory base. Given that life expectancy is increasing, there is a present interest in the search for anti-aging strategies that allow a healthy aging. Interestingly, in Spain, where the Mediterranean Diet (MD) is the reference food pattern, life expectancy will have the highest average by 2040. This diet is characterized, among other items, by virgin olive oil intake, which contains between 50-200 mg/kg of hydroxytyrosol, a major polyphenolic component of olive oil. Hydroxytyrosol is formed by the hydrolysis of oleuropein during the maturing of olives, storage of olive oil, and preparation of table olives. It is a yield of oleuropein by microbiota action in the organism after virgin olive oil consumption. The daily intake in context of the MD is estimated to be around 0.15 and 30 mg/day. In the last few years, hydroxytyrosol has received increasing attention due to its multiple pharmacological activities, such as antioxidant, anti-inflammatory and pro-apoptotic activities. It has also been the focus of extensive research regarding its bioactivity. In this sense, hydroxytyrosol is under consideration for the development of new anti-aging strategies. In this review we will summarize the potential anti-aging effects of hydroxytyrosol and its protective role in several age-related diseases.

In vivo effect of apomorphine and haloperidol on MPP neurotoxicity.

The involvement of dopaminergic (DAergic) receptor drugs in the neuroprotection against the neurotoxic action of 1-methyl-4-phenylpyridinium (MPP(+)) in the DAergic terminals in striatum was studied using an intracerebral microdialysis technique. Twenty-four hours after surgery (day 1), apomorphine and haloperidol, alone or with 1 mmol/l of MPP(+) perfusion through the microdialysis probe, were systemically administered. Forty-eight hours after surgery (day 2), 1 mmol/l of MPP(+) was perfused for 15 min in all groups of animals and the output of dopamine was measured. The amount of dopamine was directly proportional to the remaining striatal DAergic terminals. The results show that: (1) subcutaneous administration of apomorphine before MPP(+) perfusion prevented MPP(+)-induced neurotoxicity, and (2) intraperitoneal administration of haloperidol before MPP(+) perfusion did not prevent MPP(+)-induced neurotoxicity.

Peripheral inflammation increases the deleterious effect of CNS inflammation on the nigrostriatal dopaminergic system.

Evidence supports the role of inflammation in the development of neurodegenerative diseases. In this work, we are interested in inflammation as a risk factor by itself and not only as a factor contributing to neurodegeneration. We tested the influence of a mild to moderate peripheral inflammation (injection of carrageenan into the paws of rats) on the degeneration of dopaminergic neurons in an animal model based on the intranigral injection of lipopolysaccharide (LPS), a potent inflammatory agent. Overall, the treatment with carrageenan increased the effect of the intranigral injection of LPS on the loss of dopaminergic neurons in the SN along with all the other parameters studied, including: serum levels of the inflammatory markers TNF-α, IL-1ß, IL-6 and C-reactive protein; activation of microglia, expression of proinflammatory cytokines, the adhesion molecule ICAM and the enzyme iNOS, loss of astrocytes and damage to the blood brain barrier (BBB). The possible implication of BBB rupture in the increased loss of dopaminergic neurons has been studied using another Parkinson's disease animal model based on the intraperitoneal injection of rotenone. In this experiment, loss of dopaminergic neurons was also strengthened by carrageenan, without affecting the BBB. In conclusion, our data show that a mild to moderate peripheral inflammation can exacerbate the degeneration of dopaminergic neurons caused by a harmful stimulus.