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Inflammation can be resolved by pro-homeostatic lipids called specialized pro-resolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM-binding receptors were increased in patients with AD compared to age-matched controls. Individuals with Down syndrome (DS) exhibit accelerated acquisition of AD neuropathology, dementia, and neuroinflammation at an earlier age than the general population. Beneficial effects of inducing resolution in DS have not been investigated previously. The effects of the SPM resolvin E1 (RvE1) in a DS mouse model (Ts65Dn) were investigated with regard to inflammation, neurodegeneration, and memory deficits. A moderate dose of RvE1 for 4 weeks in middle-aged Ts65Dn mice elicited a significant reduction in memory loss, along with reduced levels of serum pro-inflammatory cytokines, and reduced microglial activation in the hippocampus of Ts65Dn mice but had no effects in age-matched normosomic mice. There were no observable adverse side effects in Ts65Dn or in normosomic mice. These findings suggest that SPMs may represent a novel drug target for individuals with DS and others at risk of developing AD.

Introduction Tau pathology is a major age-related event in Down syndrome with Alzheimer’s disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. Methods Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. Results The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PIB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites. Conclusions This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

Neuron-derived exosomes (NDEs) were enriched by anti-L1CAM antibody immunoabsorption from plasmas of subjects ages 18-26 yr within 1 wk after a sports-related mild traumatic brain injury (acute mTBI) ( n = 18), 3 mo or longer after the last of 2-4 mTBIs (chronic mTBI) ( n = 14) and with no recent history of TBI (controls) ( n = 21). Plasma concentrations of NDEs, assessed by counts and levels of extracted exosome marker CD81, were significantly depressed by a mean of 45% in acute mTBI ( P < 0.0001), but not chronic mTBI, compared with controls. Mean CD81-normalized NDE levels of a range of functional brain proteins were significantly abnormal relative to those of controls in acute but not chronic mTBI, including ras-related small GTPase 10, 73% decrease; annexin VII, 8.8-fold increase; ubiquitin C-terminal hydrolase L1, 2.5-fold increase; AII spectrin fragments, 1.9-fold increase; claudin-5, 2.7-fold increase; sodium-potassium-chloride cotransporter-1, 2.8-fold increase; aquaporin 4, 8.9-fold increase (3.6-fold increase in chronic mTBI); and synaptogyrin-3, 3.1-fold increase (1.3-fold increase in chronic mTBI) (all acute mTBI proteins P < 0.0001). In chronic mTBI, there were elevated CD81-normalized NDE levels of usually pathologic β-amyloid peptide 1-42 (1.6-fold, P < 0.0001), P-T181-tau (2.2-fold, P < 0.0001), P-S396-tau (1.6-fold, P < 0.01), IL-6 (16-fold, P < 0.0001), and prion cellular protein (PRPc) (5.1-fold, P < 0.0001) with lesser or greater (IL-6, PRPc) increases in acute mTBI. Increases in NDE levels of most neurofunctional proteins in acute, but not chronic, mTBI, and elevations of most NDE neuropathological proteins in chronic and acute mTBI delineated phase-specificity. Longitudinal studies of more mTBI subjects may identify biomarkers predictive of and etiologically involved in mTBI-induced neurodegeneration.-Goetzl, E. J., Elahi, F. M., Mustapic, M., Kapogiannis, D., Pryhoda, M., Gilmore, A., Gorgens, K. A., Davidson, B., Granholm, A.-C., Ledreux, A. Altered levels of plasma neuron-derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury.

Concussion or mild traumatic brain injury (mTBI) in athletes can cause persistent symptoms, known as post-concussion syndrome (PCS), and repeated injuries may increase the long-term risk for an athlete to develop neurodegenerative diseases such as chronic traumatic encephalopathy (CTE), and Alzheimer’s disease (AD). The Center for Disease Control estimates that up to 3.8 million sport-related mTBI are reported each year in the United States. Despite the magnitude of the phenomenon, there is a current lack of comprehensive prognostic indicators and research has shown that available monitoring tools are moderately sensitive to short-term concussion effects but less sensitive to long-term consequences. The overall aim of this review is to discuss novel, quantitative, and objective measurements that can predict long-term outcomes following repeated sports-related mTBIs. The specific objectives were (1) to provide an overview of the current clinical and biomechanical tools available to health practitioners to ensure recovery after mTBIs, (2) to synthesize potential biological mechanisms in animal models underlying the long-term adverse consequences of mTBIs, (3) to discuss the possible link between repeated mTBI and neurodegenerative diseases, and (4) to discuss the current knowledge about fluid biomarkers for mTBIs with a focus on novel exosomal biomarkers. The conclusions from this review are that current post-concussion clinical tests are not sufficiently sensitive to injury and do not accurately quantify post-concussion alterations associated with repeated mTBIs. In the current review, it is proposed that current practices should be amended to include a repeated symptom inventory, a cognitive assessment of executive function and impulse control, an instrumented assessment of balance, vestibulo-ocular assessments, and an improved panel of blood or exosome biomarkers.

Rhesus macaques intrabronchially inoculated with simian varicella virus (SVV), the counterpart of human varicella-zoster virus (VZV), developed primary infection with viremia and rash, which resolved upon clearance of viremia, followed by the establishment of latency. To assess the role of CD4 T cell immunity in reactivation, monkeys were treated with a single 50-mg/kg dose of a humanized monoclonal anti-CD4 antibody; within 1 week, circulating CD4 T cells were reduced from 40 to 60% to 5 to 30% of the total T cell population and remained low for 2 months. Very low viremia was seen only in some of the treated monkeys. Zoster rash developed after 7 days in the monkey with the most extensive CD4 T cell depletion (5%) and in all other monkeys at 10 to 49 days posttreatment, with recurrent zoster in one treated monkey. SVV DNA was detected in the lung from two of five monkeys, in bronchial lymph nodes from one of the five monkeys, and in ganglia from at least two dermatomes in three of five monkeys. Immunofluorescence analysis of skin rash, lungs, lymph nodes, and ganglia revealed SVV ORF63 protein at the following sites: sweat glands in skin; type II cells in lung alveoli, macrophages, and dendritic cells in lymph nodes; and the neuronal cytoplasm of ganglia. Detection of SVV antigen in multiple tissues upon CD4 T cell depletion and virus reactivation suggests a critical role for CD4 T cell immunity in controlling varicella virus latency. IMPORTANCE Reactivation of latent VZV in humans can result in serious neurological complications. VZV-specific cell-mediated immunity is critical for the maintenance of latency. Similar to VZV in humans, SVV causes varicella in monkeys, establishes latency in ganglia, and reactivates to produce shingles. Here, we show that depletion of CD4 T cells in rhesus macaques results in SVV reactivation, with virus antigens found in zoster rash and SVV DNA and antigens found in lungs, lymph nodes, and ganglia. These results suggest the critical role of CD4 T cell immunity in controlling varicella virus latency.