Rey et al. generate a mouse model for the spatial propagation of α-synuclein pathology that mimics prodromal Parkinson's disease.

Alterations in the endocannabinoid system (ECS) are thought to play a role in learning and memory impairments observed in Alzheimer's disease (AD). We aimed to determine the status of the brain ECS in the AβPPswe/PS1ΔE9 model of AD. The ECS comprises the neuromodulatory lipid endocannabinoids, anandamide and 2-arachidonoyl glycerol (2AG), which interact with the G protein-coupled type-1 and type-2 cannabinoid receptors. Using mass spectrometry, we quantified endocannabinoid levels and assessed lipidomic profiles of the frontal cortex, hippocampus, and striatum of 4-8 month old wildtype and AβPPswe/PS1ΔE9 mice to determine whether regional variations in endocannabinoids and lipid metabolism are observed with age and disease progression. Additionally, open-field activity, performance in the contextual fear conditioning task, and various other tasks assessing spatial and recognition memory were examined to determine the influence of age and pathology on these parameters. At all ages, AβPPswe/PS1ΔE9 mice were significantly hyperactive in the open-field and acquired contextual fear as well as wildtype mice, reflecting intact associative learning. They, however, exhibited enhanced contextual fear memory and reduced contextual fear extinction regardless of age. Disturbances in striatal lipid metabolism were observed in 6 and 8 month old AβPPswe/PS1ΔE9 mice. Endocannabinoids increased significantly with age in the hippocampus and frontal cortex of both genotypes. 8 month old AβPPswe/PS1ΔE9 mice displayed significantly lower levels of striatal 2AG than wildtype mice, but greater cannabinoid receptor/effector coupling. This study shows that alterations in lipid metabolism and endocannabinoid signaling develop with age in AβPPswe/PS1ΔE9 mice, possibly contributing to the development of AD-like behavioral deficits.

The ECs (endocannabinoids) AEA (anandamide) and 2-AG (2-arachidonoylglycerol) and their lipid congeners OEA (N-oleoylethanolamide) and PEA (N-palmitoylethanolamide) are multifunctional lipophilic signalling molecules. The ECs, OEA and PEA have multiple physiological roles including involvement in learning and memory, neuroinflammation, oxidative stress, neuroprotection and neurogenesis. They have also been implicated in the pathology of, or perhaps protective responses to, neurodegenerative diseases. This is particularly the case with Alzheimer's disease, the most common age-related dementia associated with impairments in learning and memory accompanied by neuroinflammation, oxidative stress and neurodegeneration. The present mini-review examines the evidence supporting the roles that ECs appear to play in Alzheimer's disease and the potential for beneficial therapeutic manipulation of the EC signalling system.

34Intraneuronal accumulation of α-synuclein (αSyn) is key in the pathogenesis of Parkinson's disease 35 (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and 36propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms 37 underlying the accumulation of αSyn remain unknown but evidence is growing that immune pathways 38 and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory 39 bowel disease (IBD) exhibit αSyn accumulation in their colon. We then confirmed in an experimental 40 model of IBD that intestinal inflammation can trigger αSyn accumulation in the ENS of wildtype and 41 αSyn transgenic mice. We discovered that the type and degree of inflammation modulates the extent 42 of αSyn accumulation in the colon and that macrophage-related signaling limits this process. 43Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated 44 phospho-Serine 129 αSyn in the midbrain, including the substantia nigra, in 21-month but not 9-45 month-old αSyn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-46 immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a 47 critical role for intestinal inflammation in the initiation and progression of PD. 48 49 Grathwohl et al. Results 101 IBD patients show αSyn accumulation in the ENS and local macrophages 102Recent epidemiological data links inflammatory bowel disease (IBD) to an increased risk of 103 developing PD (36)(37)(38). In order to explore if IBD is associated with enteric αSyn accumulation we 104 performed immunohistochemistry for αSyn in cryo-sections from colonic biopsies of patients with 105 ulcerative colitis (UC, n = 11, mean age 31 years), Crohn's disease (CD, n = 11; mean age 35 years), 106 and from healthy subjects (HS, n = 8; mean age 51 years). We observed in eight UC cases various 107 degrees of αSyn accumulation, mostly in neuritic structures (Figure 1). Interestingly, the eight UC 108 cases, and four patients with CD (images not shown) also showed marked intracellular αSyn staining 109 in many infiltrating monocytic cells. In contrast, only one HS showed a few immunoreactive cells 110 (images not shown). This finding in human tissue suggests a potential role of local inflammation in 111 the development of enteric αSyn accumulation. 112 113 Experimental IBD exacerbates αSyn load in submucosal plexus of αSyn transgenic and wildtype 114 mice 115 During the process of further characterizing a (Thy1)-h[A30P]αSyn transgenic mouse line (39) we 116 detected human αSyn accumulation in all innervated organs that were analyzed (Supplemental 117

The gastrointestinal tract may be a site of origin for α-synuclein pathology in idiopathic Parkinson’s disease (PD). Disruption of the autophagy-lysosome pathway (ALP) may contribute to α-synuclein aggregation. Here we examined epigenetic alterations in the ALP in the appendix by deep sequencing DNA methylation at 521 ALP genes. We identified aberrant methylation at 928 cytosines affecting 326 ALP genes in the appendix of individuals with PD and widespread hypermethylation that is also seen in the brain of individuals with PD. In mice, we find that DNA methylation changes at ALP genes induced by chronic gut inflammation are greatly exacerbated by α-synuclein pathology. DNA methylation changes at ALP genes induced by synucleinopathy are associated with the ALP abnormalities observed in the appendix of individuals with PD specifically involving lysosomal genes. Our work identifies epigenetic dysregulation of the ALP which may suggest a potential mechanism for accumulation of α-synuclein pathology in idiopathic PD.

Background : Intraneuronal accumulation of a-synuclein (αSyn) is key in Parkinson’s disease (PD) pathogenesis. The pathogenic process is suggested to begin in the enteric nervous system decades before diagnosis of PD and then propagate into the brain. The triggers for these events are unclear but, in some patients, colitis might play a critical role. Methods : We administered lipopolysaccharide (LPS) or dextran sulfate sodium (DSS) to assess the effect of different types of experimental colitis on αSyn accumulation in the gut of αSyn transgenic and wild type mice and quantified local gene expression by RT-PCR and level of αSyn accumulation by immunofluorescence imaging. Immune modulation during the DSS colitis paradigm in the αSyn transgenic mice included genetic ablation of Cx3cr1 or treatment with recombinant IL-10. To determine long-term effects of experimental colitis, we induced DSS colitis in young αSyn transgenic mice and aged them under normal conditions up to nine or 21 months before analyzing their brains by immunohistochemistry. In vivo experiments were performed in randomized cohorts. Blinded experimenters performed image analysis and statistical analysis depended on data type (i.e., Student’s t-test, ANOVA, mixed-effects model). Results : We demonstrate that mild sustained or one strong insult of experimental DSS colitis triggers αSyn accumulation in the submucosal plexus of wild type and αSyn transgenic mice, while short-term mild DSS experimental colitis or inflammation induced by LPS does not have such an effect. Lack of macrophage-related Cx3cr1-signalling during DSS colitis increases accumulation of αSyn in the colonic submucosal plexus of αSyn transgenic mice while systemic treatment with immune-dampening IL-10 ameliorates this phenomenon. Additionally, DSS colitis-induced αSyn accumulation in young αSyn transgenic mice persists for months and is exacerbated by lack of Cx3cr1-signaling. Remarkably, experimental colitis at three months of age exacerbates the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain (including the substantia nigra), in 21- but not 9-month-old αSyn transgenic mice. This increase in midbrain αSyn accumulation is accompanied by the loss of tyrosine hydroxylase-immunoreactive nigral neurons. Conclusions : Our data suggest that specific types of intestinal inflammation, mediated by monocyte/macrophage signaling, could play a critical role in the initiation and progression of PD.

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