Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed to suggest that functional microbial amyloid proteins produced in the gut may cross-seed Ab aggregation and prime the innate immune system to have an enhanced and pathogenic response to neuronal amyloids. In this commentary, we summarize the molecular mechanisms by which the microbiota may initiate and sustain the pathogenic processes of neurodegeneration in aging.

Key Points: Long-term effects of cisplatin are understudied. This study is the first to examine the role of macrophages in cisplatin-induced fibrosis. Depletion of kidney-resident macrophages ameliorated cisplatin-induced fibrosis, whereas depletion of infiltrating macrophages had no effect. This study highlights a pathogenic role for kidney-resident M2 macrophages in the development of fibrosis with repeated nephrotoxic injury. Background: Cisplatin-induced kidney injury remains a major obstacle in utilizing cisplatin as a chemotherapeutic for solid-organ cancers. Thirty percent of patients treated with cisplatin develop acute kidney injury (AKI), and even patients who do not develop AKI are at risk for long-term declines in kidney function and development of chronic kidney disease (CKD). Modeling cisplatin-induced kidney injury in mice has revealed that repeated low doses of cisplatin lead to development of kidney fibrosis. This model can be used to examine AKI-to-CKD transition processes. Macrophages play a role in some of these processes, including immune response, wound healing, and tissue remodeling. Depleting macrophage populations in the kidney reduced fibrosis development in other models of renal fibrosis. Methods: We used either C57BL/6 mice with a Ccr2 genetic knockout or liposome encapsulated clodronate (Clodrosome) to deplete macrophage populations during repeated 9 mg/kg cisplatin treatments. We assessed how immune cell populations were altered in the blood and kidney of these mice and how these alterations affected development of renal fibrosis and kidney injury. Results: We found that Clodrosome treatment decreased collagen deposition, myofibroblast accumulation, and inflammatory cytokine production, whereas Ccr2 genetic knockout had no effect on these markers after cisplatin treatment. Additionally, Ccr2^−/− mice had decreased levels of F4/80^lo infiltrating macrophages in the kidney after cisplatin treatments, but Clodrosome treatment depleted F4/80^hi resident and CD206⁺ M2 macrophages. Conclusions: These data suggest that Clodrosome depletion of F4/80^hi and M2 macrophages in the kidney attenuates development of renal fibrosis after repeated low doses of cisplatin.

Fine particulate matter (PM_2.5) air pollution exposure increases the cardiovascular disease risk. Although the specific mechanisms remain elusive, it is thought that PM_2.5-induced oxidative stress and endothelial dysfunction contribute to this pathogenesis. Our previous findings indicate that PM_2.5 impairs vascular health via a circulating factor and that plasma lipid changes contribute to the observed vascular effects. In the current study, we extend on these findings by further characterizing PM_2.5-induced changes in circulating lipids and examining whether the observed changes were accompanied by related alterations in the liver transcriptome. To address the role of pulmonary oxidative stress, we exposed wild-type (WT) mice and mice that overexpress extracellular superoxide dismutase (ecSOD-Tg) in the lungs to concentrated ambient PM_2.5 (CAP, 9 days). We found that CAP decreased circulating complex lipids and increased free fatty acids and acylcarnitines in WT, but not ecSOD-Tg mice. These plasma lipid changes were accompanied by transcriptional changes in genes that regulate lipid metabolism (eg, upregulation of lipid biosynthesis, downregulation of mitochondrial/peroxisomal FA metabolism) in the liver. The CAP-induced changes in lipid homeostasis and liver transcriptome were accompanied by pulmonary but not hepatic oxidative stress and were largely absent in ecSOD-Tg mice. Our results suggest that PM_2.5 impacts hepatic lipid metabolism; however, it remains unclear whether the transcriptional changes in the liver contribute to PM_2.5-induced changes in plasma lipids. Regardless, PM_2.5-induced changes in the plasma lipidome and hepatic transcriptome are, at least in part, mediated by pulmonary oxidative stress.

Nonmotor symptoms (NMS) in Parkinsons disease (PD) can start up to a decade before motor manifestations and strongly correlate with the quality of life. Understanding patterns of NMS can provide clues to the incipient site of PD pathology. Our goal was to systematically characterize the progression of NMS in PD (n=489), compared to healthy controls, HC (n=241), based on the sex of the subjects and laterality of motor symptom onset. Additionally, NMS experienced at the onset of PD were also compared to subjects with scans without dopaminergic deficit, SWEDD (n=81). The Parkinsons Progression Markers Initiative (PPMI) database was utilized to analyze several NMS scales. NMS experienced by PD and SWEDD cohorts were significantly higher than HC and both sex and laterality influenced several NMS scales at the onset of motor symptoms. Sex Differences. PD males experienced significant worsening of sexual, urinary, sleep, and cognitive functions compared to PD females. PD females reported significantly increased thermoregulatory dysfunction and anxious mood over 7 years and significantly more constipation during the first 4 years after PD onset. Laterality Differences. At onset, PD subjects with right-sided motor predominance reported significantly higher autonomic dysfunction. Subjects with left-sided motor predominance experienced significantly more anxious mood at onset which continued as Parkinsons progressed. In conclusion, males experienced increased NMS burden in Parkinsons disease. Laterality of motor symptoms did not significantly influence NMS progression, except anxious mood. We analyzed NMS in a large cohort of PD patients, and these data are valuable to improve PD patients quality of life by therapeutically alleviating nonmotor symptoms.