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ObjectiveParkinson’s disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson’s from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson’s disease, multiple system atrophy and other proteinopathies.MethodsWe performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson’s and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.ResultsMean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson’s disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson’s disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson’s disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson’s disease progression.ConclusionsIncreased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson’s disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson’s disease from atypical parkinsonism.

A robust top down proteomics method is presented for profiling alpha-synuclein species from autopsied human frontal cortex brain tissue from Parkinson's cases and controls. The method was used to test the hypothesis that pathology associated brain tissue will have a different profile of post-translationally modified alpha-synuclein than the control samples. Validation of the sample processing steps, mass spectrometry based measurements and data processing steps were performed. The intact protein quantitation method features extraction and integration of m/z data from each charge state of a detected alpha-synuclein species and fitting of the data to a simple linear model which accounts for concentration and charge state variability. The quantitation method was validated with serial dilutions of intact protein standards. Using the method on the human brain samples, several previously unreported modifications in alpha-synuclein were identified. Low levels of phosphorylated alpha synuclein were detected in brain tissue fractions enriched for Lewy body pathology and were marginally significant between PD cases and controls (p = 0.03).

Background Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer’s disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks. Methods Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing. Four age groups of mice (2-, 4-, 6-, and 8-months) were analyzed to capture longitudinal gene expression changes that correspond to varying levels of pathology, from minimal tau accumulation to massive neuronal loss. Statistical and system biology approaches were used to analyze the genes and pathways that underlie microglia activation. Differentially expressed genes were compared to human brain co-expression networks. Results Statistical analysis of RNAseq data indicated that more than 4000 genes were differentially expressed in rTg4510 microglia compared to wild type microglia, with the majority of gene expression changes occurring between 2- and 4-months of age. These genes belong to four major clusters based on their temporal expression pattern. Genes involved in innate immunity were continuously up-regulated, whereas genes involved in the glutamatergic synapse were down-regulated. Up-regulated innate inflammatory pathways included NF-κB signaling, cytokine-cytokine receptor interaction, lysosome, oxidative phosphorylation, and phagosome. NF-κB and cytokine signaling were among the earliest pathways activated, likely driven by the RELA , STAT1 and STAT6 transcription factors. The expression of many AD associated genes such as APOE and TREM2 was also altered in rTg4510 microglia cells. Differentially expressed genes in rTg4510 microglia were enriched in human neurodegenerative disease associated pathways, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, and highly overlapped with the microglia and endothelial modules of human brain transcriptional co-expression networks. Conclusion This study revealed temporal transcriptome alterations in microglia cells in response to pathological tau perturbation and provides insight into the molecular changes underlying microglia activation during tau mediated neurodegeneration.

The mouse mammary gland is a complex tissue, which is continually undergoing changes in structure and function. Embryonically, the gland begins with invasion of the underlying fat pad by a rudimentary ductal structure. Postnatal growth occurs in two phases: ductal growth and early alveolar development during estrous cycles, and cycles of proliferation, differentiation, and death that occur with each pregnancy, lactation, and involution. The variety of epithelial structures and stromal changes throughout the life of a mammary gland makes it a challenge to study. The purpose of this histological review is to give a brief representation of the morphological changes that occur throughout the cycle of mouse mammary gland development so that developmental changes observed in mouse models of mammary development can be appreciated.

A lack of initial and long-term training has compromised the ability of special education paraeducators (paras) who work with emotionally and behaviorally disturbed (EBD) students. This Participatory Action Research Study asked the special education paraeducators to share their input on what they believed they needed in training to improve their ability to deliver quality social and academic education to EBD students at Kerry Middle School.Using social justice through a trauma-informed teaching framework, special education paras were asked to comment on the quality and quantity of initial and professional development training they had received. From the qualitative data, an intervention was developed to address the paras' concerns for more training. The scale of this intervention currently applies to the special education paras at KMS. However, other school districts may find the study results and subsequent intervention of value.

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-β peptide A[β.sub.42]. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of A[β.sub.42] produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered A[β.sub.42]. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of A[β.sub.42] in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce A[β.sub.42] through inhibition of Rho activity.

Rare heterozygous coding variants in the Triggering Receptor Expressed in Myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial-gene enriched subnetwork at 4 months, including a shift towards a more central role for the Amyloid Precursor Protein (App) gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signalling hub, suggesting an underlying link between immune response and vascular disease in dementia.

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-[beta] peptide A[[beta].sub.42]. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of A[[beta].sub.42] produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered A[[beta].sub.42]. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of A[[beta].sub.42] in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce A[[beta].sub.42] through inhibition of Rho activity.

A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-β peptide Aβ 42 . We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Aβ 42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Aβ 42 . Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Aβ 42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Aβ 42 through inhibition of Rho activity.