Fig. 2.Transformants releasing E␤C suffered less damage than control lines when EPNs were present. (A) Root damage measured on plants that had received neither WCR eggs nor nematodes was minimal, and there was no difference between transformed and nontransformed plants (n ϭ 5, P ϭ 0.87). (B) Root damage on plants that received only WCR eggs, but no nematodes, was substantial. Again, no significant difference was found between the transformed and nontransformed plants (n ϭ 5, P ϭ 0.18). (C) In plots that received WCR eggs and H. megidis, roots from transformed plants (pooled) had significantly less damage than roots from control lines (n ϭ 30, P ϭ 0.007). Approximately one-quarter of the transformed plants were found not to emit E␤C. Removing these plants from the statistical analysis did not significantly affect the results. The letters above the bars indicate significant differences within a graph. Error bars indicate standard errors.

Abnormal neuronal aggregation of ␣-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive ␣-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial ␣-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that ␣-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of ␣-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human ␣-synuclein. Furthermore, astrocytes that were exposed to neuronal ␣-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of ␣-synuclein. Together, these results suggest that astroglial ␣-synuclein pathology is produced by direct transmission of neuronal ␣-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

Accumulation of the synaptic protein ␣-synuclein (␣-syn) is a hallmark of Parkinson's disease (PD) and Lewy body disease (LBD),

SUMMARY Metabolites in the kynurenine pathway of tryptophan degradation are thought to play an important role in neurodegenerative disorders such as Alzheimer’s disease and Huntington’s disease. Metabolites that cause glutamate receptor-mediated excitotoxicity and free radical formation are elevated in the blood and vulnerable brain regions in these diseases, while levels of the neuroprotective metabolite kynurenic acid are often decreased. Here we describe the synthesis and characterization of JM6, a novel small-molecule pro-drug inhibitor of kynurenine 3-monooxygenase (KMO). JM6 raises kynurenic acid and reduces extracellular glutamate in the brain after chronic oral administration by inhibiting KMO in blood. In a transgenic mouse model of Alzheimer’s disease, JM6 prevented spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extended life span, prevented synaptic loss, and decreased microglial activation in a mouse model of Huntington’s disease. These findings support a critical link between blood cells and neurodegeneration that is mediated by KMO and the kynurenine pathway.

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are common causes of motor and cognitive deficits and are associated with the abnormal accumulation of alpha-synuclein (α-syn). This study investigated whether passive immunization with a novel monoclonal α-syn antibody (9E4) against the C-terminus (CT) of α-syn was able to cross into the CNS and ameliorate the deficits associated with α-syn accumulation. In this study we demonstrate that 9E4 was effective at reducing behavioral deficits in the water maze, moreover, immunization with 9E4 reduced the accumulation of calpain-cleaved α-syn in axons and synapses and the associated neurodegenerative deficits. In vivo studies demonstrated that 9E4 traffics into the CNS, binds to cells that display α-syn accumulation and promotes α-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of α-syn may be of therapeutic relevance in patients with PD and DLB.