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  patients across the AD spectrum in the large human European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) cohort (n = 310). Intriguingly, the extracellular matrix protein decorin was similarly and significantly increased in both App-NL-F and App-NL-G-F mice, strikingly already in three months old App-NL-F mice and in preclinical AD subjects having abnormal CSF- Aβ42 but normal cognition. Notably, in this group of subjects, CSF- decorin levels positively correlated with CSF-Aβ42 levels indicating that the change in CSF-decorin is associated with early Aβ amyloidosis. In addition, CSF-decorin highly correlated with both CSF-t-Tau and CSF- p-Tau. Importantly, receiver operating characteristic analysis revealed that CSF-decorin can predict a specific AD subtype having innate immune activation and potential choroid plexus dysfunction in the brain. Consistently, in App-NL-F mice, increased CSF-decorin correlated with both Aβ plaque load and with decorin levels in choroid plexus. In addition, a low concentration of human Aβ42 induces decorin secretion from mouse primary neurons. Interestingly, we finally identify decorin to activate neuronal autophagy through enhancing lysosomal function. Altogether, the increased CSF-decorin levels occurring at an early stage of Aβ amyloidosis in the brain may reflect pathological changes in choroid plexus, present in a subtype of AD subjects for which decorin could serve as potential CSF biomarker.
Background: Down Syndrome is caused by the 21 chromosome trisomy and the population with this syndrome is highly vulnerable to early cognitive decline. The aim of this study was to evaluate the brain inflammation of an animal model of Down syndrome (Ts65Dn) across lifespan, by Positron Emission Tomography (PET) with [11C]PK11195, and correlate with memory data, obtained by recognition object tests. Materials and Methods: Ts65Dn mice of different ages: 2 (n=7), 5 (n=3), 14 (n=5), 20 (n=4) and 24 (n= 3) months were imaged in a small animal PET scanner 30 min after intravenous injection of [11C]PK11195 (±18 MBq) and the short and long-term memories were assessed by object recognition test [1]. Whole brain [11C]PK11195 uptake is presented in SUV (Standardized Uptake Value) and correlations with memory index were tested by Pearson´s correlation. Statistical differences were considered significant when P≤0.05.
Results: There was an increased [11C]PK11195 uptake in animals of 14 months-months-old compared to the age of 2 months (0.69±0.23 vs 0.36±0.12; p=0.02). These increased neuroinflammation at age of 14 months was strongly associated with a worse short-memory index (r= -0.9616 and p=0.009).
Discussion: Neuroinflammation can contribute to cognitive decline independent of the pathology [1-3]. In Down syndrome, neuroinflammation can anticipate and aggravate cognitive decline [4-8], but the neuroinflammation data has never been measured by PET imaging in Down syndrome before, as far we could identity, what makes this study very interesting in associating in vivo image data and memory performance. It is also interesting to mention that the association was identified only with short-term memory indicating that the inflammation has an acute effect over the memory.
Conclusions: Our results suggest that increased neuroinflammation interferes with the performance of animals in the object recognition test, indicating that brain inflammation impairs the short-term memory of Ts65Dn Down syndrome animal model.
Neuronal oxidative stress (OS), caused by the aberrant upregulation of reactive oxygen species (ROS), is a common theme among neurodegenerative diseases. ROS damages lipids to produce toxic, peroxidated (O2--) lipids that need resolution to maintain cell health. Recently, we found that glia can help to resolve O2--lipids sourced from neurons, protecting the neurons from degeneration1. Specifically, the O2--lipids are transferred from stressed neurons to glia via apolipoproteins, including APOE1,2. Within glia, the O2--lipids are sequestered into lipid droplets (LD) and resolved. Numerous Alzheimer’s disease (AD) risk factors mediate this process and their loss leaves neurons susceptible to damage3,4. Further, abundant glial LD were described to occur in AD brains by Alois Alzheimer5,6. We are now expanding studies to define potential interactions between glial LD formation and the important disease protein, Tau. In many neurodegenerative diseases, Tau becomes inhibited due to its hyperphosphorylation and aggregation. Using Drosophila melanogaster and human iPSC-derived astrocytes we were surprised to find that Tau is expressed in glia, independent of exposure to neurons. Interestingly, glial Tau is critical for the formation of LD during neuronal OS. By TEM, the absence of glial Tau results in morphological defects of retinal glia in young flies in response to neuronal OS and these cells degenerate with sustained neuronal OS in old flies. As tauopathies are primarily considered gain-of-function diseases, we further found that expression of human Tau in glia of flies and in mouse astrocytes can similarly inhibit glial LD formation during neuronal OS. Morphological defects of fly retinal glia in response to neuronal OS and human Tau expression is seen by TEM. While investigations are continuing, this work demonstrates that glial Tau plays an important, conserved role during the resolution of neuronal OS and has implications in many neurodegenerative diseases.
Astrocytes show phenotypic and functional changes in response to injury and disease. Whilst not fully understood, these changes can be used to classify astrocytes as quiescent or reactive. Extracellular vesicles (EVs) are small membrane bound vesicles containing protein, RNA and metabolites which are released from all cell types and are thought to reflect the phenotype of the cell at time of release. Therefore, astrocyte- derived extracellular vesicles (ADEVs) could act as biomarkers for CNS disease and may be involved in disease transmission. In vitro models typically use fetal bovine serum (FBS) to culture healthy astrocytes, however serum may induce astrocyte reactivity. This project aims to investigate the effect of serum on human astrocytes and their ADEVs. Primary human astrocytes were cultured in serum-free or serum media and characterised using ICC, qPCR and RNA-SEQ. ADEVs were collected from both models and isolated using ultrafiltration followed by size exclusion chromatography. ADEVs were then characterised using
Glial and vascular contributions to neurodegenerative diseases
    PP37
Tau mediates the neuroprotective process of glial lipid droplet formation during neuronal oxidative stress
Lindsey Goodman1,2, Isha Ralhan3, Zhongyuan Zuo1,2, Oguz Kanca1,2, Ye-Jin Park1,2, Matthew Moulton1,2, Maria Ioannou3, Hugo Bellen1,2
1Baylor College Of Medicine, Texas, USA, 2Jan and Dan Duncan Neurological Research Institute, Houston, Texas, 3University of Alberta, Edmonton, Canada
   PP36
Increased neuroinflammation is related to memory impairment in Down syndrome animal model
Larissa Estessi De Souza1, Manuella Penido da Silva1, Caroline Cristiano Real1, Carlos Alberto Buchpiguel1,
Daniele de Paula Faria1
1Universidade De São Paulo, São Paulo, Brazil
   PP38
The effect of serum on human astrocyte reactivity and their extracellular vesicles in vitro
Katherine White1, Daniel Scott1, Robert Layfield1,
Sebastien Serres1
1School of Life Sciences, University Of Nottingham, Nottingham, United Kingdom
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