Background Alzheimer disease (AD) and Parkinson disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood. Methods Tau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by Single Molecule Array technology with 303 subjects. Results The efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls, and correlated with cerebrospinal fluid tau. Conclusions Tau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

Alzheimer's disease (AD) and Lewy body diseases (LBD), e.g. Parkinson's disease (PD) dementia and dementia with Lewy bodies (DLB), are common causes of geriatric cognitive impairments. In addition, AD and LBD are often found in the same patients at autopsy; therefore, biomarkers that can detect the presence of both pathologies in living subjects are needed. In this investigation, we report the assessment of α-synuclein (α-syn) in cerebrospinal fluid (CSF) and its association with CSF total tau (t-tau), phosphorylated tau181 (p-tau181), and amyloid beta1-42 (Aβ1-42) in subjects of the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=389), with longitudinal clinical assessments. A strong correlation was noted between α-syn and t-tau in controls, as well as in patients with AD and mild cognitive impairment (MCI). However, the correlation is not specific to subjects in the ADNI cohort, as it was also seen in PD patients and controls enrolled in the Parkinson's Progression Markers Initiative (PPMI; n=102). A bimodal distribution of CSF α-syn levels was observed in the ADNI cohort, with high levels of α-syn in the subjects with abnormally increased t-tau values. Although a correlation was also noted between α-syn and p-tau181, there was a mismatch (α-syn-p-tau181-Mis), i.e. higher p-tau181 levels accompanied by lower α-syn levels in a subset of ADNI patients. We hypothesize that this α-syn-p-tau181-Mis is a CSF signature of concomitant LBD pathology in AD patients. Hence, we suggest that inclusion of measures of CSF α-syn and calculation of α-syn-p-tau181-Mis improves the diagnostic sensitivity/specificity of classic CSF AD biomarkers and better predicts longitudinal cognitive changes.

The A/VN/1203/04 H5N1 influenza virus is capable of infecting the CNS of mice and inducing a number of neurodegenerative pathologies. Here, we examined the effects of H5N1 on several pathological aspects affected in parkinsonism, including loss of the phenotype of dopaminergic (DAergic) neurons located in the substantia nigra pars compacta (SNpc), expression of mono- and indolamines in brain, alterations in SNpc microglia number and morphology, and expression of cytokines, chemokines and growth factors. We find that H5N1 induces a transient loss of the DAergic phenotype in SNpc and now report that this loss recovers by 90 days post infection (dpi). A similar pattern of loss and recovery was seen in monoamine levels of the basal ganglia. The inflammatory response in lung and different regions of the brain known to be targets of the H5N1 virus (brainstem, substantia nigra, striatum, and cortex) were examined at 3, 10, 21, 60 and 90 dpi. We found a significant increase in the number of activated microglia in each of these brain regions that lasted at least 90 days. We also quantified expression of IL-1α, IL-1β, IL-2, IL-6, IL-9, IL-10, IL-12(p70), IL-13, TNF-α, IFN-γ, GM-CSF, G-CSF, M-CSF, eotaxin, IP-10, KC, MCP-1, MIP-1α, MIP-1β and VEGF and find that the pattern and levels of expression are dependent on both brain region and time after infection. We conclude that H5N1 infection in mice induces a long-lasting inflammatory response in brain and may play a contributing factor in the development of pathologies in neurodegenerative disorders.

In addition to amyloid beta (Aβ) and tau, α-synuclein, best known for its role in Parkinson’s disease (PD), has been suggested to be involved in cognition and pathogenesis of Alzheimer’s disease (AD). We investigate the potential of α-synuclein in cerebrospinal fluid (CSF) as a biomarker of cognitive decline in AD, and its prodromal phase, mild cognitive impairment (MCI). Using an established, sensitive Luminex assay, we measured α-synuclein levels in the CSF of a cohort of close to 400 healthy control, MCI and AD subjects obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and factored in APOE genotype in data analysis. CSF α-synuclein levels were significantly higher in the MCI (P = 0.005) and AD (P < 0.001) groups, compared to controls. However, receiver operating characteristic (ROC) curve analysis suggests that CSF α-synuclein level on its own only offered modest sensitivity (65 %) and specificity (74 %) as a diagnostic marker of AD, with an area under the curve (AUC) value of 0.719 for AD vs controls. The effect of APOE genotype, if any, was quite subtle. However, there was a significant correlation between α-synuclein and cognition (P = 0.001), with increased α-synuclein levels associated with decreased MMSE scores. Our results support a role for α-synuclein even in MCI, the early phase of AD, in addition to being a potential contributor in MCI and AD diagnosis or monitoring of disease progression.

Recently, α-synuclein (α-syn) and DJ-1, two proteins critically involved in Parkinson’s disease (PD), have been shown to be present in saliva, suggesting their potential utility as biomarkers of PD. However, the origin and influence of demographic characteristics (e.g., age or gender) on these proteins are unknown. We identified cheek epithelium, which forms the majority of the cellular component of saliva and is readily accessible clinically, as one of several potential sources of salivary α-syn and DJ-1. However, no PD-related trend in the cellular component was present. In the supernatant collected from 198 healthy subjects, no correlation was seen between salivary DJ-1 or α-syn with age. When male and female subjects were analyzed separately, a weak age-dependent increase in DJ-1 level was present in male subjects, along with slightly increased α-syn in female subjects. These results, though largely negative, provide critical information for understanding the salivary gland pathology and saliva as a PD biomarker source, and must be considered in future investigations of salivary changes in PD.

Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain-of-function of the androgen receptor (AR). In a prior study we showed that coregulator binding through the activation function-2 (AF2) domain of AR is essential to pathogenesis, suggesting that AF2 may be a druggable target for selective modulation of toxic AR activity. Here we screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function, and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice showed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain, and spinal cord. In a preclinical trial in a novel mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity, and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy, and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.

Background Meso Scale Discovery (MSD) recently established electrochemiluminescence-based assays to measure cerebrospinal fluid (CSF) levels of total tau (t-tau) and amyloid beta 1–42 peptide (Aβ42) that can aid in the diagnosis of Alzheimer’s disease (AD). The goal of this investigation is to independently evaluate this platform and establish cut-off values of these biomarkers for AD diagnosis. Objective To validate the analytical and clinical performance of the MSD t-tau and Aβ42 kits and propose diagnostic cut-off values for the field. Methods The analytical performance of the CSF t-tau and Aβ42 assays was determined, followed by assessment of diagnostic performance of CSF t-tau, Aβ42 and t-tau/Aβ42 in three clinically characterized cohorts. Results Both MSD assays demonstrated consistent and stable analytical performance, as well as resistance to several important pre-analytic variables. Diagnostically, t-tau/Aβ42 performed the best. Conclusions Our results independently confirm the analytical and clinical performance of the MSD CSF t-tau and Aβ42 assays. Based on a large, multi-center, clinically diagnosed cohort, we propose for the first time candidate diagnostic cut-offs for MSD measured CSF t-tau, Aβ42 and t-tau/Aβ42. However, these values needs to be refined as more subjects are included and the assays are tested by other laboratories.

Highlights d Decreased G3BP reduces stress granule formation and increases stress tolerance d MAGE-B2 represses G3BP mRNA translation by displacing DDX5 helicase from the 5 0 UTR d The mouse ortholog of MAGE-B2 regulates stemness of testis spermatogonial stem cells d Excess G3BP results in hypersensitivity to heat stress and reduced fertility in vivo