Sleep-disordered breathing is highly prevalent in the elderly population. Obstructive sleep apnea (OSA) represents the most common sleep disorder among the adult and elderly population. Recently, OSA ...diagnosis has been associated with an increased risk of developing cognitive decline and dementia, including vascular dementia and Alzheimer's disease (AD). Subsequently, there have been studies on AD biomarkers investigating cerebrospinal fluid, blood, neuroimaging, and nuclear medicine biomarkers in patients with OSA. Furthermore, studies have attempted to assess the possible effects of continuous positive airway pressure (CPAP) treatment on the cognitive trajectory and AD biomarkers in patients with OSA. This review summarizes the findings of studies on each AD biomarker (cognitive, biofluid, neuroimaging, and nuclear medicine imaging) in patients with OSA, also accounting for the related effects of CPAP treatment. In addition, the hypothetical model connecting OSA to AD in a bi-directional interplay is analyzed. Finally, the sex-based differences in prevalence and clinical symptoms of OSA between men and women have been investigated in relation to AD risk. Further studies investigating AD biomarkers changes in patients with OSA and the effect of CPAP treatment should be auspicated in future for identifying strategies to prevent the development of AD.
Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous ...system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain's pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3-CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.
Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity ...deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long-term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β) perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This survey takes into consideration the most recent advances in both human degenerative ataxias, disorders with a well established cerebellar origin, and discoveries from dystonia rodent models ...aimed at discussing the pathogenesis of dystonia.
One common recurrent term that emerges when describing dystonia is heterogeneity. Indeed, dystonia encompasses a wide group of 'hyperkinetic' movement disorders, with heterogeneous causes, classification, anatomical and physiological substrates. In addition, the clinical heterogeneity of age at onset, symptom distribution and appearance of non-motor symptoms has supported the concept of dystonia as 'network' disorder. Pathophysiological alterations are thought to arise from dysfunction at cortico-thalamic-basal ganglia level, whereas, more recently, a role for cerebellar pathways emerged. Results from human and animal studies thus fuel the evolving concept of the network disorder.
Current evidence suggests the involvement of multiple brain regions and cellular mechanisms, as part of the neural dysfunction observed at system level in dystonia.
It is well-appreciated that phosphorylation is an essential post-translational mechanism of regulation for several proteins, including group 1 metabotropic glutamate receptors (mGluRI), mGluR1, and ...mGluR5 subtypes. While contributions of various serine/threonine protein kinases on mGluRI modulation have been recognized, the functional role of tyrosine kinases (TKs) is less acknowledged. Here, while describing current evidence supporting that mGluRI are targets of TKs, we mainly focus on the modulatory roles of the ErbB tyrosine kinases receptors-activated by the neurotrophic factors neuregulins (NRGs)-on mGluRI function. Available evidence suggests that mGluRI activity is tightly dependent on ErbB signaling, and that ErbB's modulation profoundly influences mGluRI-dependent effects on neurotransmission, neuronal excitability, synaptic plasticity, and learning and memory processes.
Dopamine (DA) is a key neurotransmitter modulating essential functions of the central nervous system (CNS), like voluntary movement, reward, several cognitive functions and goal-oriented behaviors. ...The factual relevance of DAergic transmission can be well appreciated by considering that its dysfunction is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson's disease (PD) and associated movement disorders, as well as, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we present an overview of the current knowledge on the involvement of DAergic receptors in the regulation of key physiological brain activities, and the consequences of their dysfunctions in brain disorders such as PD, schizophrenia and addiction.
Objective: The complex nature of Parkinson's disease (PD) makes difficult to rate its severity, mainly based on the visual inspection of motor impairments. Wearable sensors have been demonstrated to ...help overcoming such a difficulty, by providing objective measures of motor abnormalities. However, up to now, those sensors have been used on advanced PD patients with evident motor impairment. As a novelty, here we report the impact of wearable sensors in the evaluation of motor abnormalities in newly diagnosed, untreated, namely de novo, patients. Methods: A network of wearable sensors was used to measure motor capabilities, in 30 de novo PD patients and 30 healthy subjects, while performing five motor tasks. Measurement data were used to determine motor features useful to highlight impairments and were compared with the corresponding clinical scores. Three classifiers were used to differentiate PD from healthy subjects. Results: Motor features gathered from wearable sensors showed a high degree of significance in discriminating the early untreated de novo PD patients from the healthy subjects, with 95% accuracy. The rates of severity obtained from the measured features are partially in agreement with the clinical scores, with some highlighted, though justified, exceptions. Conclusion: Our findings support the feasibility of adopting wearable sensors in the detection of motor anomalies in early, untreated, PD patients. Significance: This work demonstrates that subtle motor impairments, occurring in de novo patients, can be evidenced by means of wearable sensors, providing clinicians with instrumental tools as suitable supports for early diagnosis, and subsequent management.
Dopamine D2 receptor signaling is central for striatal function and movement, while abnormal activity is associated with neurological disorders including the severe early‐onset DYT1 dystonia. ...Nevertheless, the mechanisms that regulate D2 receptor signaling in health and disease remain poorly understood. Here, we identify a reduced D2 receptor binding, paralleled by an abrupt reduction in receptor protein level, in the striatum of juvenile Dyt1 mice. This occurs through increased lysosomal degradation, controlled by competition between β‐arrestin 2 and D2 receptor binding proteins. Accordingly, we found lower levels of striatal RGS9‐2 and spinophilin. Further, we show that genetic depletion of RGS9‐2 mimics the D2 receptor loss of DYT1 dystonia striatum, whereas RGS9‐2 overexpression rescues both receptor levels and electrophysiological responses in Dyt1 striatal neurons. This work uncovers the molecular mechanism underlying D2 receptor downregulation in Dyt1 mice and in turn explains why dopaminergic drugs lack efficacy in DYT1 patients despite significant evidence for striatal D2 receptor dysfunction. Our data also open up novel avenues for disease‐modifying therapeutics to this incurable neurological disorder.
Synopsis
Striatal dopamine D2 receptor (DRD2) dysfunction in DYT1 dystonia mouse models was uncovered and shown to be mediated by an abnormal and selective trafficking to lysosomal degradation. The regulatory protein RGS9‐2 over‐expression can restore both the striatal level and the function of DRD2.
Correlated developmental changes in the expression level of DRD2 and its regulatory protein RGS9‐2 are observed in wild‐type mouse striatum.
A simultaneous reduction in striatal DRD2 and RGS9‐2 protein expression levels is observed in adult Dyt1 mouse models.
DRD2 downregulation is mediated by its selective trafficking to lysosomal degradation.
Viral‐induced expression of RGS9‐2 is able to restore both the expression level and function of striatal DRD2.
Striatal dopamine D2 receptor (DRD2) dysfunction in DYT1 dystonia mouse models was uncovered and shown to be mediated by an abnormal and selective trafficking to lysosomal degradation. The regulatory protein RGS9‐2 over‐expression can restore both the striatal level and the function of DRD2.
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