Aims Parkinson’s disease and related disorders are devastating neurodegenerative pathologies. Since α‐synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made to clarify the pathogenic mechanisms of α‐synuclein's detrimental effects. α‐synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co‐fostering Parkinson’s disease. However, direct evidence linking inflammation to the harmful activities of α‐synuclein oligomers or to the Parkinson’s disease behavioural phenotype is lacking. Methods To clarify whether neuroinflammation influences Parkinson’s disease pathogenesis, we developed: (i) a ‘double‐hit’ approach in C57BL/6 naive mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic ‘double‐hit’ model where lipopolysaccharides were given to A53T α‐synuclein transgenic Parkinson’s disease mice. Results Lipopolysaccharides induced a long‐lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS‐activated microglia and astrocytes responded differently to the oligomers with microglia activating further and acquiring a pro‐inflammatory M1 phenotype, while astrocytes atrophied. In the transgenic ‘double‐hit’ A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally induced neuroinflammation potentiates the α‐synuclein oligomer’s actions and aggravates cognitive deficits in A53T mice. Conclusions The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α‐synucleinopathies.

Mechanisms of tissue damage in Huntington's disease involve excitotoxicity, mitochondrial damage, and inflammation, including microglia activation. Immunomodulatory and anti-protein aggregation properties of tetracyclines were demonstrated in several disease models. In the present study, the neuroprotective and anti-inflammatory effects of the tetracycline doxycycline were investigated in the mouse model of HD disease R6/2. Transgenic mice were daily treated with doxycycline 20 mg/kg, starting from 4 weeks of age. After sacrifice, histological and immunohistochemical studies were performed. We found that doxycycline-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the saline-treated ones. Primary outcome measures such as striatal atrophy, neuronal intranuclear inclusions, and the negative modulation of microglial reaction revealed a neuroprotective effect of the compound. Doxycycline provided a significantly increase of activated CREB and BDNF in the striatal neurons, along with a down modulation of neuroinflammation, which, combined, might explain the beneficial effects observed in this model. Our findings show that doxycycline treatment could be considered as a valid therapeutic approach for HD.

Scope Amyloid‐β oligomers (AβO) are causally related to Alzheimer's disease (AD). Dietary natural compounds, especially flavonoids and flavan‐3‐ols, hold great promise as potential AD‐preventive agents but their host and gut microbiota metabolism complicates identification of the most relevant bioactive species. This study aims to investigate the ability of a comprehensive set of phenyl‐γ‐valerolactones (PVL), the main circulating metabolites of flavan‐3‐ols and related dietary compounds in humans, to prevent AβO‐mediated toxicity. Methods and results The anti‐AβO activity of PVLs is examined in different cell model systems using a highly toxic β‐oligomer‐forming polypeptide (β23) as target toxicant. Multiple PVLs, and particularly the monohydroxylated 5‐(4′‐hydroxyphenyl)‐γ‐valerolactone metabolite [(4′‐OH)‐PVL], relieve β‐oligomer‐induced cytotoxicity in yeast and mammalian cells. As revealed by atomic force microscopy (AFM) and other in vitro assays, (4′‐OH)‐PVL interferes with AβO (but not fibril) assembly and actively remodels preformed AβOs into nontoxic amorphous aggregates. In keeping with the latter mode of action, treatment of AβOs with (4′‐OH)‐PVL prior to brain injection strongly reduces memory deterioration as well as neuroinflammation in a mouse model of AβO‐induced memory impairment. Conclusion PVLs, which have been validated as biomarkers of the dietary intake of flavan‐3‐ols, lend themselves as novel AβO‐selective, candidate AD‐preventing compounds.

No abstract

A cytokine storm drives the pathogenesis of severe COVID-19 infection and several biomarkers have been linked to mortality. Chronic kidney disease (CKD) emerged as a risk factor for severe COVID-19. We investigated the association between selected biomarkers and mortality in 77 patients hospitalized for COVID-19, and whether they differ in patients with eGFR higher and lower than 45 mL/min. The association between patients’ characteristics, plasma biomarkers and mortality was conducted by univariate logistic regression models and independent predictors of mortality were then used to create a multivariate prediction model through Cox regression. Patients with lower eGFR had a significant increase of GDF-15, CD-25 and RAGE, with higher plasma levels in non-survivors and in patients who needed ventilation. At univariate analysis, low and mid-low GDF-15 quartiles (<4.45 ng/mL) were associated with lower mortality risk, while mid-high and high quartiles (>4.45 ng/mL) were associated with higher mortality risk. Independent association between GDF-15 quartiles and mortality risk was confirmed in the Cox model and adjusted for eGFR, age, fever and dyspnea (HR 2.28, CI 1.53–3.39, p < 0.0001). The strength of the association between GDF-15 quartiles and mortality risk increased in patients with lower compared to higher eGFR (HR 2.53, CI 1.34–4.79 versus HR 1.99, CI 1.17–3.39). Our findings may suggest a further investigation of the effect of GDF-15 signaling pathway inhibition in CKD.