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Ageing is the main risk factor common to most primary neurodegenerative disorders. Indeed, age-related brain alterations have been long considered to predispose to neurodegeneration. Although protein misfolding and the accumulation of toxic protein aggregates have been contemplated as causative events in neurodegeneration, several biological pathways affected by brain ageing are also contributing to pathogenesis. Here, we discuss the evidence showing the involvement of the mechanisms controlling neuronal structure, gene expression, autophagy, cell metabolism, and neuroinflammation in the onset and progression of neurodegenerative disorders. Furthermore, we review the therapeutic strategies currently under development or as future approaches designed to normalize these pathways, which may then boost brain resilience to cope with toxic protein species. Therefore, in addition to therapies targeting the insoluble protein aggregates specifically associated with each neurodegenerative disorder, these novel pharmacological approaches may be part of combined therapies designed to rescue brain function.

Background Recent studies support the therapeutic utility of repetitive transcranial magnetic stimulation in Parkinson's disease (PD), whose progression is correlated with loss of corticostriatal long-term potentiation and long-term depression. Glial cell activation is also a feature of PD that is gaining increasing attention in the field because astrocytes play a role in chronic neuroinflammatory responses but are also able to manage dopamine (DA) levels. Methods Intermittent theta-burst stimulation protocol was applied to study the effect of therapeutic neuromodulation on striatal DA levels measured by means of in vivo microdialysis in 6-hydroxydopamine-hemilesioned rats. Effects on corticostriatal synaptic plasticity were studied through in vitro intracellular and whole-cell patch clamp recordings while stepping test and CatWalk were used to test motor behavior. Immunohistochemical analyses were performed to analyze morphological changes in neurons and glial cells. Results Acute theta-burst stimulation induced an increase in striatal DA levels in hemiparkinsonian rats, 80 minutes post-treatment, correlated with full recovery of plasticity and amelioration of motor performances. With the same timing, immediate early gene activation was restricted to striatal spiny neurons. Intense astrocytic and microglial responses were also significantly reduced 80 minutes following theta-burst stimulation. Conclusion Taken together, these results provide a first glimpse on physiological adaptations that occur in the parkinsonian striatum following intermittent theta-burst stimulation and may help to disclose the real potential of this technique in treating PD and preventing DA replacement therapy-associated disturbances. © 2017 International Parkinson and Movement Disorder Society.

Zinc (Zn(2+) ) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn(2+) homeostasis is critical and involves different classes of molecules, including Zn(2+) transporters. The ubiquitous Zn(2+) transporter-1 (ZNT-1) is a transmembrane protein that pumps cytosolic Zn(2+) to the extracellular space, but its function in the central nervous system is not fully understood. Here, we show that ZNT-1 interacts with GluN2A-containing NMDA receptors, suggesting a role for this transporter at the excitatory glutamatergic synapse. First, we found that ZNT-1 is highly expressed at the hippocampal postsynaptic density (PSD) where NMDA receptors are enriched. Two-hybrid screening, coimmunoprecipitation experiments and clustering assay in COS-7 cells demonstrated that ZNT-1 specifically binds the GluN2A subunit of the NMDA receptor. GluN2A deletion mutants and pull-down assays indicated GluN2A(1390-1464) domain as necessary for the binding to ZNT-1. Most importantly, ZNT-1/GluN2A complex was proved to be dynamic, since it was regulated by induction of synaptic plasticity. Finally, modulation of ZNT-1 expression in hippocampal neurons determined a significant change in dendritic spine morphology, PSD-95 clusters and GluN2A surface levels, supporting the involvement of ZNT-1 in the dynamics of excitatory PSD. Zn(2+) transporter-1 (ZNT-1) pumps cytosolic Zn(2+) to the extracellular space, but its function in the central nervous system is not fully understood. We show that ZNT-1 interacts with GluN2A-containing NMDA receptors at the glutamatergic synapse. Most importantly, ZNT-1/GluN2A complex is regulated by induction of synaptic plasticity. Modulation of ZNT-1 expression in hippocampal neurons determined a shrinkage of dendritic spines and a reduction of GluN2A surface levels supporting the involvement of ZNT-1 in the dynamics of the excitatory synapse.