Activation of microglia by classical inflammatory mediators can convert astrocytes to a neurotoxic A1 phenotype in a variety of neurological diseases1,2. Development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat these diseases for which there are no disease modifying therapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists have been touted as potential neuroprotective agents for neurologic disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD)3-13. The mechanisms by which GLP-1R agonists are neuroprotective are not known. Here we show that a potent, brain penetrant long acting GLP-1R agonist NLY01 protects against the loss of dopamine neurons and behavioral deficits in the α-synuclein preformed fibril (α-syn PFF) model of sporadic PD14,15. NLY01 also prolongs the life and reduces the behavioral deficits and neuropathological abnormalities in the human A53T α-synuclein (hA53T) transgenic (Tg) model of α-synucleinopathy induced neurodegeneration16. We found that NLY01 is a potent GLP-1R agonist with favorable properties that is neuroprotective via the direct prevention of microglial mediated conversion of astrocytes to an A1 neurotoxic phenotype. In light of NLY01 favorable properties it should be evaluated in the treatment of PD and related neurologic disorders characterized by microglial activation.

Highlights d Gut-to-brain propagation of pathologic a-synuclein via the vagus nerve causes PD d Dopamine neurons degenerate in the pathologic a-synuclein gut-to-brain model of PD d Gut injection of pathologic a-synuclein causes PD-like motor and non-motor symptoms d PD-like pathology and symptoms require endogenous a-synuclein

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Though emerging evidence indicates that the pathogenesis of Parkinson's disease is strongly correlated to the accumulation and transmission of α-synuclein (α-syn) aggregates in the midbrain, no anti-aggregation agents have been successful at treating the disease in the clinic. Here, we show that graphene quantum dots (GQDs) inhibit fibrillization of α-syn and interact directly with mature fibrils, triggering their disaggregation. Moreover, GQDs can rescue neuronal death and synaptic loss, reduce Lewy body and Lewy neurite formation, ameliorate mitochondrial dysfunctions, and prevent neuron-to-neuron transmission of α-syn pathology provoked by α-syn preformed fibrils. We observe, in vivo, that GQDs penetrate the blood-brain barrier and protect against dopamine neuron loss induced by α-syn preformed fibrils, Lewy body/Lewy neurite pathology and behavioural deficits.

Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of α-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of α-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of α-syn tetramers. Here, we show that accumulation of GSLs due to GBA1 deficiency decreases α-syn tetramers and related multimers and increases α-syn monomers in CRISPR-GBA1 knockout (KO) SH-SY5Y cells. Moreover, α-syn tetramers and related multimers are decreased in N370S Parkinson's disease (PD) induced pluripotent stem cell (iPSC)-derived human dopaminergic (hDA) neurons and murine neurons carrying the heterozygous L444P mutation. Treatment with miglustat to reduce GSL accumulation and overexpression of GBA1 to augment GBA1 activity reverse the destabilization of α-syn tetramers and protect against α-syn preformed fibril-induced toxicity in hDA neurons. Taken together, these studies provide mechanistic insights into how GBA1 regulates the transition from monomeric α-syn to α-syn tetramers and multimers and suggest unique therapeutic opportunities for PD and dementia with Lewy bodies.

BackgroundMutations in glucocerebrosidase (GBA) cause Gaucher disease (GD) and increase the risk of developing Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Since both genetic and environmental factors contribute to the pathogenesis of sporadic PD, we investigated the susceptibility of nigrostriatal dopamine (DA) neurons in L444P GBA heterozygous knock-in (GBA+/L444P) mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a selective dopaminergic mitochondrial neurotoxin.MethodWe used GBA+/L444P mice, α-synuclein knockout (SNCA−/−) mice at 8 months of age, and adeno-associated virus (AAV)-human GBA overexpression to investigate the rescue effect of DA neuronal loss and susceptibility by MPTP. Mitochondrial morphology and functional assay were used to identify mitochondrial defects in GBA+/L444P mice. Motor behavioral test, immunohistochemistry, and HPLC were performed to measure dopaminergic degeneration by MPTP and investigate the relationship between GBA mutation and α-synuclein. Mitochondrial immunostaining, qPCR, and Western blot were also used to study the effects of α-synuclein knockout or GBA overexpression on MPTP-induced mitochondrial defects and susceptibility.ResultsL444P GBA heterozygous mutation reduced GBA protein levels, enzymatic activity and a concomitant accumulation of α-synuclein in the midbrain of GBA+/L444P mice. Furthermore, the deficiency resulted in defects in mitochondria of cortical neurons cultured from GBA+/L444P mice. Notably, treatment with MPTP resulted in a significant loss of dopaminergic neurons and striatal dopaminergic fibers in GBA+/L444P mice compared to wild type (WT) mice. Levels of striatal DA and its metabolites were more depleted in the striatum of GBA+/L444P mice. Behavioral deficits, neuroinflammation, and mitochondrial defects were more exacerbated in GBA+/L444P mice after MPTP treatment. Importantly, MPTP induced PD-like symptoms were significantly improved by knockout of α-synuclein or augmentation of GBA via AAV5-hGBA injection in both WT and GBA+/L444P mice. Intriguingly, the degree of reduction in MPTP induced PD-like symptoms in GBA+/L444Pα-synuclein (SNCA)−/− mice was nearly equal to that in SNCA−/− mice after MPTP treatment.ConclusionOur results suggest that GBA deficiency due to L444P GBA heterozygous mutation and the accompanying accumulation of α-synuclein render DA neurons more susceptible to MPTP intoxication. Thus, GBA and α-synuclein play dual physiological roles in the survival of DA neurons in response to the mitochondrial dopaminergic neurotoxin, MPTP.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0233-5) contains supplementary material, which is available to authorized users.

Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40-induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40-induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy.

Microglia play a critical role in controlling the homeostasis of the brain, but over-activated microglia secrete pro-inflammatory mediators and cytokines, which induce neuronal cell death. Fucoxanthin (Fx), a marine carotenoid, has demonstrated a variety of beneficial health effects. Despite accumulating evidence supporting the immune-modulating effects of Fx in vitro, the underlying signaling pathways remain unknown. In the present study, Fx dose-dependently inhibited the secretion of lipopolysaccharide (LPS)-induced pro-inflammatory mediators including interleukin (IL)-6, tumor necrosis factor (TNF)-α, reactive oxygen species (ROS), prostaglandin (PG) E, and nitric oxide (NO) productions, and also suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 enzymes. Further, the reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated IL-6, TNF-α, iNOS, and COX-2 mRNA expression were suppressed by treatment with Fx in a dose-dependently manner. The mechanism studies indicated that Fx blocks protein kinase B (Akt)/nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPKs)/transcription factor (AP)-1 pathways. In addition, we demonstrated that Fx increases nuclear factor erythroid 2-related factor (Nrf)-2 activation and heme oxygenase (HO)-1 expression in LPS-activated BV-2 microglia. Subsequently, we found that Fx also mediates the reactive oxygen species (ROS) by activating protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) pathway, and promotes the production of brain-derived neurotrophic factor (BDNF). These results indicate that Fx may be more effective and potential than other candidates via either decreasing the pro-inflammatory factors production or increasing the neuroprotective molecules expression for therapy of neurodegenerative diseases.