Region-specific changes in gene expression are associated with cognitive deficits in the alpha-synuclein-induced model of Parkinson's disease: A transcriptomic profiling study.

Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, which weakens the development and administration of proper therapies. In an α-synuclein (αSyn)-based model of PD featuring early motor and cognitive impairments, we investigated the transcriptome profile of brain regions involved in PD with cognitive deficits, via a transcriptomic analysis based on RNA sequencing (RNA-seq) technology. Rats infused in the substantia nigra with human α-synuclein oligomers (H-SynOs) developed mild cognitive deficits after three months, as measured by the two-trial recognition test in a Y-maze and the novel object recognition test. RNA-seq analysis showed that 17,436 genes were expressed in the anterior cingulate cortex (ACC) and 17,216 genes in the hippocampus (HC). In the ACC, 51 genes were differentially expressed between vehicle and H-αSynOs treated samples, which showed N= 21 upregulated and N = 30 downregulated genes. In the HC, 104 genes were differentially expressed, the majority of them not overlapping with DEGs in the ACC, with N = 41 upregulated and N = 63 downregulated in H-αSynOs-treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related with immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Immunofluorescence analysis confirmed the decreased expression of CD68 within microglial cells. In contrast, the most significantly enriched terms in the HC were mainly involved in mitochondrial homeostasis, potassium voltage-gated channel, cytoskeleton and fiber organisation, suggesting that the gene expression in the neuronal population was mostly affected in this region in early disease stages. Altogether results show that H-αSynOs trigger a region-specific dysregulation of gene expression in ACC and HC, providing a pathological substrate for MCI associated with early PD.

Genetic and Molecular Regulations of Neuronal Activity.

This Special Issue of the International Journal of Molecular Sciences (IJMS) focuses on 'Genetic and Molecular Regulations of Neuronal Activity' [...].

Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2.

Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5-mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2-ERK1/2 interactions.

Induction of Activity-Regulated Cytoskeleton-Associated Protein and c-Fos Expression in an Animal Model of Anorexia Nervosa.

Anorexia nervosa (AN) is a complex eating disorder characterized by reduced caloric intake to achieve body-weight loss. Furthermore, over-exercise is commonly reported. In recent years, animal models of AN have provided evidence for neuroplasticity changes in specific brain areas of the mesocorticolimbic circuit, which controls a multitude of functions including reward, emotion, motivation, and cognition. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates several forms of synaptic plasticity and has been linked to neuropsychiatric illness. Since the role of Arc in AN has never been investigated, in this study we evaluated whether the anorexic-like phenotype reproduced by the activity-based anorexia (ABA) model may impact its expression in selected brain regions that belong to the mesocorticolimbic circuit (i.e., prefrontal cortex, nucleus accumbens, and hippocampus). The marker of neuronal activation c-Fos was also assessed. We found that the expression of both markers increased in all the analyzed brain areas of ABA rats in comparison to the control groups. Moreover, a negative correlation between the density of Arc-positive cells and body-weight loss was found. Together, our findings suggest the importance of Arc and neuroplasticity changes within the brain circuits involved in dysfunctional behaviors associated with AN.

Combined measure of salivary alpha-synuclein species as diagnostic biomarker for Parkinson's disease.

Parkinson's disease (PD) diagnosis is still vulnerable to bias, and a definitive diagnosis often relies on post-mortem neuropathological diagnosis. In this regard, alpha-synuclein (αsyn)-specific in vivo biomarkers remain a critical unmet need, based on its relevance in the neuropathology. Specifically, content changes in αsyn species such as total (tot-αsyn), oligomeric (o-αsyn), and phosphorylated (p-αsyn) within the cerebrospinal fluid (CSF) and peripheral fluids (i.e., blood and saliva) have been proposed as PD biomarkers possibly reflecting the neuropathological outcome. Here, we measured the p-αsyn levels in the saliva from 15 PD patients along with tot-αsyn, o-αsyn and their ratios, and compared the results with those from 23 healthy subjects (HS), matched per age and sex. We also calculated the optimal cutoff values for different αsyn species to provide information about their capability to discriminate PD from HS. We found that p-αsyn was the most abundant alpha-synuclein species in the saliva. While p-αsyn concentration did not differ between PD and HS when adjusted for total salivary proteins, the ratio p-αsyn/tot-αsyn was largely lower in PD patients than in HS. Moreover, the concentration of o-αsyn was increased in the saliva of PD patients, and tot-αsyn did not differ between PD and HS. The ROC curves indicated that no single αsyn form or ratio could provide an accurate diagnosis of PD. On the other hand, the ratio of different items, namely p-αsyn/tot-αsyn and o-αsyn, yielded more satisfactory diagnostic accuracy, suggesting that the combined measure of different species in the saliva may show more promises as a diagnostic means for PD.

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex.

Parkinson's disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease's motor and non-motor aspects. Here, we show that the bilateral intracerebral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc) offers a valid model for studying the cognitive symptoms of PD, which adds to the classical motor aspects previously described in the same model. Indeed, H-αSynOs-infused rats displayed memory deficits in the two-trial recognition task in a Y maze and the novel object recognition (NOR) test performed three months after the oligomer infusion. In the anterior cingulate cortex (ACC) of H-αSynOs-infused rats the in vivo electrophysiological activity was altered and the expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) and the AMPA receptor subunit GluR1 were decreased. The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in cognition-related regions such as the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. We found an increased GFAP reactivity and the acquisition of a proinflammatory phenotype by microglia, as indicated by the increased levels of microglial Tumor Necrosis Factor alpha (TNF-α) as compared to vehicle-infused rats. Moreover, diffused deposits of phospho-alpha synuclein (p-αSyn) and Lewy neurite-like aggregates were found in the SNpc and striatum, suggesting the spreading of toxic protein within anatomically interconnected areas. Altogether, we present a neuropathological rat model of PD that is relevant for the study of cognitive dysfunction featuring the disease. The intranigral infusion of toxic oligomeric species of alpha-synuclein (α-Syn) induced spreading and neuroinflammation in distant cognition-relevant regions, which may drive the altered neuronal activity underlying cognitive deficits.

BDNF Alterations in Brain Areas and the Neurocircuitry Involved in the Antidepressant Effects of Ketamine in Animal Models, Suggest the Existence of a Primary Circuit of Depression.

Major depressive disorder is one of the primary causes of disability and disease worldwide. The therapy of depression is prevalently based on monoamine reuptake blockers; consequently, investigations aimed to clarify the aetiology of depression have mostly looked at brain areas innervated by monamines and brain circuitry involved in inputs and outputs of these areas. The recent approval of esketamine as a rapid-acting antidepressant drug in treatment-resistant depression, has definitively projected glutamatergic transmission as a key constituent in the use of new drugs in antidepressant therapy. In this review we have examined the role of several brain areas: namely, the hippocampus, the medial Prefrontal Cortex (mPFC), the nucleus accumbens (NAc), the Lateral Habenula (LHb), the amygdala and the Bed Nucleus of Stria Terminalis (BNST). The reason for undertaking an in-depth review is due to their significant role in animal models of depression, which highlight their inter-connections as well as their inputs and outputs. In particular, we examined the modification of the expression and release of the brain derived neurotrophic factor (BDNF) and associated changes in dendritic density induced by chronic stress in the above areas of animal models of depression (AnMD). We also examined the effectiveness of ketamine and standard antidepressants in reversing these alterations, with the aim of identifying a brain circuit where pathological alteration might trigger the appearance of depression symptoms. Based on the role that these brain areas play in the generation of the symptoms of depression, we assumed that the mPFC, the NAc/Ventral Tegmental Area (VTA) and the hippocampus form a primary circuit of depression, where regular performance can endure resilience to stress. We have also examined how this circuit is affected by environmental challenges and how the activation of one or more areas, including amygdala, LHb or BNST can produce local detrimental effects that spread over specific circuits and generate depression symptoms. Furthermore, we also examined how, through their outputs, these three areas can negatively influence the NAc/VTA-PFC circuit directly or through the BNST, to generate anhedonia, one of the most devastating symptoms of depression.

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease.

Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.

Repurposing Ketamine in Depression and Related Disorders: Can This Enigmatic Drug Achieve Success?

Repurposing ketamine in the therapy of depression could well represent a breakthrough in understanding the etiology of depression. Ketamine was originally used as an anesthetic drug and later its use was extended to other therapeutic applications such as analgesia and the treatment of addiction. At the same time, the abuse of ketamine as a recreational drug has generated a concern for its psychotropic and potential long-term effects; nevertheless, its use as a fast acting antidepressant in treatment-resistant patients has boosted the interest in the mechanism of action both in psychiatry and in the wider area of neuroscience. This article provides a comprehensive overview of the actions of ketamine and intends to cover: (i) the evaluation of its clinical use in the treatment of depression and suicidal behavior; (ii) the potential use of ketamine in pediatrics; (iii) a description of its mechanism of action; (iv) the involvement of specific brain areas in producing antidepressant effects; (v) the potential interaction of ketamine with the hypothalamic-pituitary-adrenal axis; (vi) the effect of ketamine on neuronal transmission in the bed nucleus of stria terminalis and on its output; (vii) the evaluation of any gender-dependent effects of ketamine; (viii) the interaction of ketamine with the inflammatory processes involved in depression; (ix) the evaluation of the effects observed with single or repeated administration; (x) a description of any adverse or cognitive effects and its abuse potential. Finally, this review attempts to assess whether ketamine's use in depression can improve our knowledge of the etiopathology of depression and whether its therapeutic effect can be considered an actual cure for depression rather than a therapy merely aimed to control the symptoms of depression.

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders.

Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

Nicotine, cocaine, amphetamine, morphine, and ethanol increase norepinephrine output in the bed nucleus of stria terminalis of freely moving rats.

The bed nucleus of stria terminalis (BNST) is a complex limbic area involved in neuroendocrine and behavioural responses and, in particular, in the modulation of the stress response. BNST is innervated by dopamine and norepinephrine, which are known to be involved in drug addiction. It is also known that several drugs of abuse increase dopamine transmission in the BNST, but there has been less research regarding the effect on norepinephrine transmission. Here, we have used the microdialysis technique to investigate the effect of several drugs of abuse on norepinephrine transmission in the BNST of freely moving rats. We observed that nicotine (0.2-0.4 mg/kg), cocaine (2.5-5 mg/kg), amphetamine (0.25-0.5 mg/kg), and ethanol (0.5-1.0 g/kg), dose-dependently increased norepinephrine output while the effect of morphine at 3.0 was lower than that of 1.0 mg/kg. These results suggest that many drugs of abuse, though possessing diverse mechanisms of action, share the property of increasing norepinephrine transmission in the BNST. Furthermore, we suggest that the recurring activation of NE transmission in the BNST, due to drug administration, contributes to the alteration of the function that BNST assumes in how the behavioural response to stress manifests, favouring the establishment of the stress-induced drug seeking.

Modeling Parkinson's Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers.

The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson's disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.

Metabolomics Fingerprint Induced by the Intranigral Inoculation of Exogenous Human Alpha-Synuclein Oligomers in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is considered a synucleinopathy because of the intraneuronal accumulation of aggregated α-synuclein (αSyn). Recent evidence points to soluble αSyn-oligomers (αSynO) as the main cytotoxic species responsible for cell death. Given the pivotal role of αSyn in PD, αSyn-based models are crucial for the investigation of toxic mechanisms and the identification of new therapeutic targets in PD. By using a metabolomics approach, we evaluated the metabolic profile of brain and serum samples of rats infused unilaterally with preformed human αSynOs (HαSynOs), or vehicle, into the substantia nigra pars compacta (SNpc). Three months postinfusion, the striatum was dissected for striatal dopamine (DA) measurements via High Pressure Liquid Chromatography (HPLC) analysis and mesencephalon and serum samples were collected for the evaluation of metabolite content via gas chromatography mass spectrometry analysis. Multivariate, univariate and correlation statistics were applied. A 40% decrease of DA content was measured in the HαSynO-infused striatum as compared to the contralateral and the vehicle-infused striata. Decreased levels of dehydroascorbic acid, myo-inositol, and glycine, and increased levels of threonine, were found in the mesencephalon, while increased contents of fructose and mannose, and a decrease in glycine and urea, were found in the serum of HαSynO-infused rats. The significant correlation between DA and metabolite content indicated that metabolic variations reflected the nigrostriatal degeneration. Collectively, the metabolomic fingerprint of HαSynO-infused rats points to an increase of oxidative stress markers, in line with PD neuropathology, and provides hints for potential biomarkers of PD.

Can pioglitazone be potentially useful therapeutically in treating patients with COVID-19?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic disease (COVID-19) that has spread globally causing more than 30,000 deaths. Despite the immense and ongoing global effort, no efficacious drugs to fight this plague have been identified and patients admitted to the intensive care units (ICU), for respiratory distress, are managed mostly by means of supportive care based on oxygen maintenance. Several authors have reported that the prevalence of hypertension, diabetes, cardiovascular and cerebrovascular diseases comorbidities were indeed frequent among patients with COVID-19, which suggests that these conditions are likely to aggravate and complicate the prognosis. What the aforementioned diseases have in common is a latent chronic inflammatory state that may be associated with the alteration of laboratory parameters that are typical of the metabolic syndrome and insulin resistance. In severe COVID-19 patients laboratory markers of inflammation such as C-reactive protein, IL-6, D-dimer, serum ferritin and lactate dehydrogenase are elevated in many patients; assessed since the 4th-6th day of illness onset, such increases seem to be predictive of an adverse prognosis. Our hypothesis is that drugs belonging to the family of thiazolidinediones (TZD) such as pioglitazone or rosiglitazone, approved for treating the condition of insulin resistance and the accompanying inflammation, could ameliorate the prognosis of those COVID-19 patients with diabetes, hypertension and cardiovascular disorders comorbidities. TZD are PPARγ agonists that act on nuclear receptors, thereby triggering certain transcription factors. TZD were widely used for type-2 diabetes in the first decade of this century and although concerns have been raised for possible side effects associated with long-term treatment, their use has been recently revaluated for their anti-inflammatory properties in numerous medical conditions.

The role of glia in Parkinson's disease: Emerging concepts and therapeutic applications.

Originally believed to primarily affect neurons, Parkinson's disease (PD) has recently been recognized to also affect the functions and integrity of microglia and astroglia, two cell categories of fundamental importance to brain tissue homeostasis, defense, and repair. Both a loss of glial supportive-defensive functions and a toxic gain of glial functions are implicated in the neurodegenerative process. Moreover, the chronic treatment with L-DOPA may cause maladaptive glial plasticity favoring a development of therapy complications. This chapter focuses on the pathophysiology of PD from a glial point of view, presenting this rapidly growing field from the first discoveries made to the most recent developments. We report and compare histopathological and molecular findings from experimental models of PD and human studies. We moreover discuss the important role played by astrocytes in compensatory adaptations taking place during presymptomatic disease stages. We finally describe examples of potential therapeutic applications stemming from an increased understanding of the important roles of glia in PD.

Neuroprotection by the Immunomodulatory Drug Pomalidomide in the Drosophila LRRK2WD40 Genetic Model of Parkinson's Disease.

The search for new disease-modifying drugs for Parkinson's disease (PD) is a slow and highly expensive process, and the repurposing of drugs already approved for different medical indications is becoming a compelling alternative option for researchers. Genetic variables represent a predisposing factor to the disease and mutations in leucine-rich repeat kinase 2 (LRRK2) locus have been correlated to late-onset autosomal-dominant PD. The common fruit fly Drosophila melanogaster carrying the mutation LRRK2 loss-of-function in the WD40 domain (LRRK2WD40), is a simple in vivo model of PD and is a valid tool to first evaluate novel therapeutic approaches to the disease. Recent studies have suggested a neuroprotective activity of immunomodulatory agents in PD models. Here the immunomodulatory drug Pomalidomide (POM), a Thalidomide derivative, was examined in the Drosophila LRRK2WD40 genetic model of PD. Mutant and wild type flies received increasing POM doses (1, 0.5, 0.25 mM) through their diet from day 1 post eclosion, until postnatal day (PN) 7 or 14, when POM's actions were evaluated by quantifying changes in climbing behavior as a measure of motor performance, the number of brain dopaminergic neurons and T-bars, mitochondria integrity. LRRK2WD40 flies displayed a spontaneous age-related impairment of climbing activity, and POM significantly and dose-dependently improved climbing performance both at PN 7 and PN 14. LRRK2WD40 fly motor disability was underpinned by a progressive loss of dopaminergic neurons in posterior clusters of the protocerebrum, which are involved in the control of locomotion, by a low number of T-bars density in the presynaptic bouton active zones. POM treatment fully rescued the cell loss in all posterior clusters at PN 7 and PN 14 and significantly increased the T-bars density. Moreover, several damaged mitochondria with dilated cristae were observed in LRRK2WD40 flies treated with vehicle but not following POM. This study demonstrates the neuroprotective activity of the immunomodulatory agent POM in a genetic model of PD. POM is an FDA-approved clinically available and well-tolerated drug used for the treatment of multiple myeloma. If further validated in mammalian models of PD, POM could rapidly be clinically tested in humans.

Beneficial effects of curtailing immune susceptibility in an Alzheimer's disease model.

BACKGROUND: Currently, there are no effective therapeutic options for Alzheimer's disease, the most common, multifactorial form of dementia, characterized by anomalous amyloid accumulation in the brain. Growing evidence points to neuroinflammation as a major promoter of AD. We have previously shown that the proinflammatory cytokine TNFSF10 fuels AD neuroinflammation, and that its immunoneutralization results in improved cognition in the 3xTg-AD mouse. METHODS: Here, we hypothesize that inflammatory hallmarks of AD might parallel with central and peripheral immune response dysfunction. To verify such hypothesis, we used a triple transgenic mouse model of AD. 3xTg-AD mice were treated for 12 months with an anti-TNFSF10 antibody, and thereafter immune/inflammatory markers including COX2, iNOS, IL-1ß and TNF-α, CD3, GITR, and FoxP3 (markers of regulatory T cells) were measured in the spleen as well as in the hippocampus. RESULTS: Spleens displayed accumulation of amyloid-ß1-42 (Aß1-42), as well as high expression of Treg cell markers FoxP3 and GITR, in parallel with the increased levels of inflammatory markers COX2, iNOS, IL-1ß and TNF-α, and blunted IL-10 expression. Moreover, CD3 expression was increased in the hippocampus, consistently with FoxP3 and GITR. After chronic treatment of 3xTg-AD mice with an anti-TNFSF10 antibody, splenic FoxP3, GITR, and the above-mentioned inflammatory markers expression was restored to basal levels, while expression of IL-10 was increased. A similar picture was observed in the hippocampus. Such improvement of peripheral and CNS inflammatory/immune response was associated with decreased microglial activity in terms of TNFα production, as well as decreased expression of both amyloid and phosphorylated tau protein in the hippocampus of treated 3xTg-AD mice. Interestingly, we also reported an increased expression of both CD3 and FoxP3, in sections from human AD brain. CONCLUSIONS: We suggest that neuroinflammation in the brain of 3xTg-AD mice triggered by TNFSF10 might result in a more general overshooting of the immune response. Treatment with an anti-TNFSF10 antibody blunted inflammatory processes both in the spleen and hippocampus. These data confirm the detrimental role of TNFSF10 in neurodegeneration, and corroborate the hypothesis of the anti-TNFSF10 strategy as a potential treatment to improve outcomes in AD.

Immunomodulatory drugs alleviate l-dopa-induced dyskinesia in a rat model of Parkinson's disease.

BACKGROUND: Thalidomide and closely related analogues are used clinically for their immunomodulatory and antiangiogenic properties mediated by the inhibition of the proinflammatory cytokine tumor necrosis factor α. Neuroinflammation and angiogenesis contribute to classical neuronal mechanisms underpinning the pathophysiology of l-dopa-induced dyskinesia, a motor complication associated with l-dopa therapy in Parkinson's disease. The efficacy of thalidomide and the more potent derivative 3,6'-dithiothalidomide on dyskinesia was tested in the 6-hydroxydopamine Parkinson's disease model. METHODS: Three weeks after 6-hydroxydopamine infusion, rats received 10 days of treatment with l-dopa plus benserazide (6 mg/kg each) and thalidomide (70 mg/kg) or 3,6'-dithiothalidomide (56 mg/kg), and dyskinesia and contralateral turning were recorded daily. Rats were euthanized 1 hour after the last l-dopa injection, and levels of tumor necrosis factor-α, interleukin-10, OX-42, vimentin, and vascular endothelial growth factor immunoreactivity were measured in their striatum and substantia nigra reticulata to evaluate neuroinflammation and angiogenesis. Striatal levels of GLUR1 were measured as a l-dopa-induced postsynaptic change that is under tumor necrosis factor-α control. RESULTS: Thalidomide and 3,6'-dithiothalidomide significantly attenuated the severity of l-dopa-induced dyskinesia while not affecting contralateral turning. Moreover, both compounds inhibited the l-dopa-induced microgliosis and excessive tumor necrosis factor-α in the striatum and substantia nigra reticulata, while restoring physiological levels of the anti-inflammatory cytokine interleukin-10. l-Dopa-induced angiogenesis was inhibited in both basal ganglia nuclei, and l-dopa-induced GLUR1 overexpression in the dorsolateral striatum was restored to normal levels. CONCLUSIONS: These data suggest that decreasing tumor necrosis factor-α levels may be useful to reduce the appearance of dyskinesia, and thalidomide, and more potent derivatives may provide an effective therapeutic approach to dyskinesia. © 2019 International Parkinson and Movement Disorder Society.

Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson's Disease?

The role of phagocytosis in the neuroprotective function of microglia has been appreciated for a long time, but only more recently a dysregulation of this process has been recognized in Parkinson's disease (PD). Indeed, microglia play several critical roles in central nervous system (CNS), such as clearance of dying neurons and pathogens as well as immunomodulation, and to fulfill these complex tasks they engage distinct phenotypes. Regulation of phenotypic plasticity and phagocytosis in microglia can be impaired by defects in molecular machinery regulating critical homeostatic mechanisms, including autophagy. Here, we briefly summarize current knowledge on molecular mechanisms of microglia phagocytosis, and the neuro-pathological role of microglia in PD. Then we focus more in detail on the possible functional role of microglial phagocytosis in the pathogenesis and progression of PD. Evidence in support of either a beneficial or deleterious role of phagocytosis in dopaminergic degeneration is reported. Altered expression of target-recognizing receptors and lysosomal receptor CD68, as well as the emerging determinant role of α-synuclein (α-SYN) in phagocytic function is discussed. We finally discuss the rationale to consider phagocytic processes as a therapeutic target to prevent or slow down dopaminergic degeneration.

Neuroinflammation in L-DOPA-induced dyskinesia: beyond the immune function.

Neuroinflammation is a main component of Parkinson's disease (PD) neuropathology, where unremitting reactive microglia and microglia-secreted soluble molecules such as cytokines, contribute to the neurodegenerative process as part of an aberrant immune reaction. Besides, pro-inflammatory cytokines, predominantly TNF-α, play an important neuromodulatory role in the healthy and diseased brain, being involved in neurotransmitter metabolism, synaptic scaling and brain plasticity. Recent preclinical studies have evidenced an exacerbated neuroinflammatory reaction in the striatum of parkinsonian rats that developed dyskinetic responses following L-DOPA administration. These findings prompted investigation of non-neuronal mechanisms of L-DOPA-induced dyskinesia (LID) involving glial cells and glial-secreted soluble molecules. Hence, besides the classical mechanisms of LID that include abnormal corticostriatal neurotransmission and maladaptive changes in striatal medium spiny neurons (MSNs), here we review studies supporting a role of striatal neuroinflammation in the development of LID, with a focus on microglia and the pro-inflammatory cytokine TNF-α. Moreover, we discuss several mechanisms that have been involved in the development of LID, which are directly or indirectly under the control of TNF-α, and might be abnormally affected by its chronic overproduction and release by microglia in PD. It is proposed that TNF-α may contribute to the altered neuronal responses occurring in LID by targeting receptor trafficking and function in MSNs, but also dopamine synthesis in preserved dopaminergic terminals and serotonin metabolism in serotonergic neurons. Therapeutic approaches specifically targeting glial-secreted cytokines may represent a novel target for preventing or treating LID.