Infiltration of immune cells to the brain and its relation to the pathogenesis of Alzheimer's and Parkinson's diseases.

The neurovascular unit, composed of vascular endothelium, vascular smooth muscle, extracellular matrix components, pericytes, astrocytes, microglia, and neurons, allows the highly regulated exchange of molecules and the limited trafficking of cells to the brain through coordinated signaling activity. The passage of peripheral immune cells to the brain parenchyma is observed when there is clear damage to the barriers of this neurovascular unit, as occurs in traumatic brain injury. The possibility of leukocyte infiltration to the brain in neurodegenerative conditions has been proposed. In this review, we focus on describing the evidence for peripheral immune cell infiltration to the brain in the two most frequent neurodegenerative diseases: Alzheimer's and Parkinson's diseases. In particular, we address the mechanisms that promote the passage of these cells into the brain under such pathological conditions. We also discuss the relevance of the resulting cellular interactions, which provide evidence that the presence of peripheral immune cells in the brain is a key point in these neurodegenerative diseases.

Early Consumption of Cannabinoids: From Adult Neurogenesis to Behavior.

The endocannabinoid system (ECS) is a crucial modulatory system in which interest has been increasing, particularly regarding the regulation of behavior and neuroplasticity. The adolescent-young adulthood phase of development comprises a critical period in the maturation of the nervous system and the ECS. Neurogenesis occurs in discrete regions of the adult brain, and this process is linked to the modulation of some behaviors. Since marijuana (cannabis) is the most consumed illegal drug globally and the highest consumption rate is observed during adolescence, it is of particular importance to understand the effects of ECS modulation in these early stages of adulthood. Thus, in this article, we sought to summarize recent evidence demonstrating the role of the ECS and exogenous cannabinoid consumption in the adolescent-young adulthood period; elucidate the effects of exogenous cannabinoid consumption on adult neurogenesis; and describe some essential and adaptive behaviors, such as stress, anxiety, learning, and memory. The data summarized in this work highlight the relevance of maintaining balance in the endocannabinoid modulatory system in the early and adult stages of life. Any ECS disturbance may induce significant modifications in the genesis of new neurons and may consequently modify behavioral outcomes.

The Hepatic Monocarboxylate Transporter 1 (MCT1) Contributes to the Regulation of Food Anticipation in Mice.

Daily recurring events can be predicted by animals based on their internal circadian timing system. However, independently from the suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system in mammals, restriction of food access to a particular time of day elicits food anticipatory activity (FAA). This suggests an involvement of other central and/or peripheral clocks as well as metabolic signals in this behavior. One of the metabolic signals that is important for FAA under combined caloric and temporal food restriction is ß-hydroxybutyrate (ßOHB). Here we show that the monocarboxylate transporter 1 (Mct1), which transports ketone bodies such as ßOHB across membranes of various cell types, is involved in FAA. In particular, we show that lack of the Mct1 gene in the liver, but not in neuronal or glial cells, reduces FAA in mice. This is associated with a reduction of ßOHB levels in the blood. Our observations suggest an important role of ketone bodies and its transporter Mct1 in FAA under caloric and temporal food restriction.

Neuronal and astroglial monocarboxylate transporters play key but distinct roles in hippocampus-dependent learning and memory formation.

Brain lactate formation, intercellular exchange and utilization has been implicated in memory formation. However, the individual role of either neuronal or astroglial monocarboxylate transporters for the acquisition and consolidation of information remains incomplete. Using novel transgenic mice and a viral vector approach to decrease the expression of each transporter in a cell-specific manner within the dorsal hippocampus, we show that both neuronal MCT2 and astroglial MCT4 are required for spatial information acquisition and retention (at 24 h post-training) in distinct hippocampus-dependent tasks. Intracerebral infusion of lactate rescued spatial learning in mice with reduced levels of astroglial MCT4 but not of neuronal MCT2, suggesting that lactate transfer from astrocytes and utilization in neurons contribute to hippocampal-dependent learning. In contrast, only neuronal MCT2 was shown to be required for long-term (7 days post training) memory formation. Interestingly, reduced MCT2 expression levels in mature neurons result in a heterologous effect as it blunts hippocampal neurogenesis associated with memory consolidation. These results suggest important but distinct contributions of both neuronal MCT2 and astroglial MCT4 in learning and memory processes, going beyond a simple passive role as alternative energy substrate suppliers or in waste product disposal.

Tanycytes Regulate Lipid Homeostasis by Sensing Free Fatty Acids and Signaling to Key Hypothalamic Neuronal Populations via FGF21 Secretion.

The hypothalamus plays a key role in the detection of energy substrates to regulate energy homeostasis. Tanycytes, the hypothalamic ependymo-glia, are located at a privileged position to integrate multiple peripheral inputs. We observed that tanycytes produce and secrete Fgf21 and are located close to Fgf21-sensitive neurons. Fasting, likely via the increase in circulating fatty acids, regulates this central Fgf21 production. Tanycytes store palmitate in lipid droplets and oxidize it, leading to the activation of a reactive oxygen species (ROS)/p38-MAPK signaling pathway, which is essential for tanycytic Fgf21 expression upon palmitate exposure. Tanycytic Fgf21 deletion triggers an increase in lipolysis, likely due to impaired inhibition of key neurons during fasting. Mice deleted for tanycytic Fgf21 exhibit increased energy expenditure and a reduction in fat mass gain, reminiscent of a browning phenotype. Our results suggest that tanycytes sense free fatty acids to maintain body lipid homeostasis through Fgf21 signaling within the hypothalamus.

Tetanus toxin C-fragment protects against excitotoxic spinal motoneuron degeneration in vivo.

The tetanus toxin C-fragment is a non-toxic peptide that can be transported from peripheral axons into spinal motoneurons. In in vitro experiments it has been shown that this peptide activates signaling pathways associated with Trk receptors, leading to cellular survival. Because motoneuron degeneration is the main pathological hallmark in motoneuron diseases, and excitotoxicity is an important mechanism of neuronal death in this type of disorders, in this work we tested whether the tetanus toxin C-fragment is able to protect MN in the spinal cord in vivo. For this purpose, we administered the peptide to rats subjected to excitotoxic motoneuron degeneration induced by the chronic infusion of AMPA in the rat lumbar spinal cord, a well-established model developed in our laboratory. Because the intraspinal infusion of the fragment was only weakly effective, whereas the i.m. administration was remarkably neuroprotective, and because the i.m. injection of an inhibitor of Trk receptors diminished the protection, we conclude that such effects require a retrograde signaling from the neuromuscular junction to the spinal motoneurons. The protection after a simple peripheral route of administration of the fragment suggests a potential therapeutic use of this peptide to target spinal MNs exposed to excitotoxic conditions in vivo.

Degeneration of spinal motor neurons by chronic AMPA-induced excitotoxicity in vivo and protection by energy substrates.

INTRODUCTION: Several data suggest that excitotoxicity due to excessive glutamatergic neurotransmission may be an important factor in the mechanisms of motor neuron (MN) death occurring in amyotrophic lateral sclerosis (ALS). We have previously shown that the overactivation of the Ca(2+)-permeable α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor type, through the continuous infusion of AMPA in the lumbar spinal cord of adult rats during several days, results in progressive rear limb paralysis and bilateral MN degeneration. Because it has been shown that energy failure and oxidative stress are involved in MN degeneration, in both ALS and experimental models of spinal MN degeneration, including excitotoxicity, in this work we tested the protective effect of the energy substrates pyruvate and ß-hydroxybutyrate (ßHB) and the antioxidants glutathione ethyl ester (GEE) and ascorbate in this chronic AMPA-induced neurodegeneration. RESULTS: AMPA infusion induced remarkable progressive motor deficits, assessed by two motor tasks, that by day seven reach bilateral rear limb paralysis. These effects correlate with the death of >80% of lumbar spinal MNs in the infused and the neighbor spinal cord segments, as well as with notable astrogliosis in the ventral horns, detected by glial fibrillary acidic protein immunohistochemistry. Co-infusion with pyruvate or ßHB notably prevented the motor deficits and paralysis, decreased MN loss to <25% and completely prevented the induction of astrogliosis. In contrast, the antioxidants tested were ineffective regarding all parameters analyzed. CONCLUSIONS: Chronic progressive excitotoxicity due to AMPA receptors overactivation results in MN death and astrogliosis, with consequent motor deficits and paralysis. Because of the notable protection against these effects exerted by pyruvate and ßHB, which are well established mitochondrial energy substrates, we conclude that deficits in mitochondrial energy metabolism are an important factor in the mechanisms of this slowly developed excitotoxic MN death, while the lack of protective effect of the antioxidants indicates that oxidative stress seems to be less significant factor. Because excitotoxicity may be involved in MN degeneration in ALS, these findings suggest possible preventive or therapeutic strategies for the disease.

Energy substrates protect hippocampus against endogenous glutamate-mediated neurodegeneration in awake rats.

Excitotoxicity due to excessive glutamatergic neurotransmission is a well-studied phenomenon that has been related to the mechanisms of neuronal death occurring in some disorders of the CNS. We have previously shown that the intrahippocampal perfusion by microdialysis of 4-aminopyridine (4-AP) in rats stimulates endogenous glutamate release from nerve endings and this results in excitotoxic effects such as immediate seizures and delayed neuronal death, due to the overactivation of N-methyl-D-aspartate (NMDA) receptors. To study whether mitochondrial energy dysfunction and oxidative stress could be involved in this 4-AP-induced excitotoxicity, we evaluated in awake rats the protective effect of several energy substrates and antioxidant compounds, using microdialysis, electroencephalographic (EEG) recording and histological analysis. The 4-AP-induced behavioral and EEG seizures, which progressed to status epilepticus in about 30 min, were prevented by the NMDA receptor antagonist MK-801, whereas acetoacetate, DL- and L-ß-hydroxybutyrate did not protect against seizures but increased the latency to the onset of status epilepticus; pyruvate, α-ketoglutarate and glutathione ethyl ester did not show any protective effect. 4-AP also produced nearly complete loss of pyramidal neurons in CA1 and CA3 regions of the ipsilateral hippocampus 24 h after the experiment. MK-801 totally prevented this neuronal death and the energy substrates tested protected by about 50%, whereas the antioxidants showed only a weak protection. We conclude that ketone bodies possess weak anticonvulsant effects and that energy metabolism impairment plays a more important role than oxidative stress in the delayed hippocampal neurodegeneration resulting from the excitotoxic action of 4-AP mediated by endogenous glutamate.