Melatonin:a multitasking indoleamine to modulate hippocampal neurogenesis

Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.

Astrocytes and retrograde degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease:removing axonal debris

Objective:The dopaminergic nigrostriatal neurons(DA cells)in healthy people present a slow degeneration with aging,which produces cellular debris throughout life.About 2%-5%of people present rapid cell degeneration of more than 50%of DA cells,which produces Parkinson's disease(PD).Neuroinflammation accelerates the cell degeneration and may be critical for the transition between the slow physiological and the rapid pathological degeneration of DA cells,particularly when it activates microglial cells of the medial forebrain bundle near dopaminergic axons.As synaptic debris produced by DA cell degeneration may trigger the parkinsonian neuroinflammation,this study investigated the removal of axonal debris produced by retrograde degeneration of DA cells,paying particular attention to the relative roles of astrocytes and microglia.Methods:Rats and mice were injected in the lateral ventricles with 6-hydroxydopamine,inducing a degeneration of dopaminergic synapses in the striatum which was not accompanied by non-selective tissue damage,microgliosis or neuroinflammation.The possible retrograde degeneration of dopaminergic axons,and the production and metabolization of DA-cell debris were studied with immunohistochemical methods and analyzed in confocal and electron microscopy images.Results:The selective degeneration of dopaminergic synapses in the striatum was followed by a retrograde degeneration of dopaminergic axons whose debris was found within spheroids of the medial forebrain bundle.These spheroids retained mitochondria and most(e.g.,tyrosine hydroxylase,the dopamine transporter protein,and amyloid precursor protein)but not all(e.g.,α-synuclein)proteins of the degenerating dopaminergic axons.Spheroids showed initial(autophagosomes)but not late(lysosomes)components of autophagy(incomplete autophagy).These spheroids were penetrated by astrocytic processes of the medial forebrain bundle,which provided the lysosomes needed to continue the degradation of dopaminergic debris.Finally,dopaminergic proteins were observed in the cell somata of astrocytes.No microgliosis or microglial phagocytosis of debris was observed in the medial forebrain bundle during the retrograde degeneration of dopaminergic axons.Conclusions:The present data suggest a physiological role of astrocytic phagocytosis of axonal debris for the medial forebrain bundle astrocytes,which may prevent the activation of microglia and the spread of retrograde axonal degeneration in PD.

A new player in the beneficial effects of exercise on the aged brain

In a recent article in Science,Horowitz et al.identify glycosylphosphatidylinositol(GPI)-degrading enzyme Gpld1 as the most critical player in the blood that can transfer the effects of exercise on adult neurogenesis and cognition to sedentary aged mice.They also demonstrate the importance of this liver-to-brain axis in ameliorating age-related regenerative and cognitive impairments.