Progression Of Neuropathology Research Articles

Comparative Evaluation of Neuropathological Lesions Progression in Different Brain Areas in A Rat Model of Chronic Hepatic Encephalopathy

Hepatic encephalopathy (HE) is considered a serious clinical complication of acute and chronic liver injury. Previous researches elucidated HE but the characterization of neuropathology in different brain areas is limited. The present study is conducted to evaluate the progression of neuropathological lesions in different brain areas in a rat model with liver fibrosis induced by thioacetamide (TAA). For this experiment, 20 male rats were divided into two groups control and TAA-treated group that was I.P injected twice a week with 100 mg/kg.b.w TAA dissolved in saline for 3 months. Three rats from each group were euthanized after 3 months and the liver specimens were collected for ensuring the development of a rat model for liver fibrosis. The remained rats were kept without further treatment with TAA for 2 months, rats were carefully monitored for abnormal signs. After the end of the experimental period, rats were euthanized and the brains were collected for histopathological examination. Microscopic examination of the brain revealed various neuropathological lesions that varied in severity between different brain areas. The most severe lesions were recorded in the midbrain and pons while mild lesions were detected in the cerebral cortex and striatum. The brain lesions comprised varied degrees of neuronal degeneration with marked astroglial and microglial reactions in the different brain regions. The obvious inflammatory reaction indicates that neuroinflammation plays an important role in the mediation of HE.

Comparative Evaluation of Neuropathological Lesions Progression in Different Brain Areas in A Rat Model of Chronic Hepatic Encephalopathy

Comparative Evaluation of Neuropathological Lesions Progression in Different Brain Areas in A Rat Model of Chronic Hepatic Encephalopathy

Computational modeling of tau pathology spread reveals patterns of regional vulnerability and the impact of a genetic risk factor.

Neuropathological staging studies have suggested that tau pathology spreads through the brain in Alzheimer's disease (AD) and other tauopathies, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute. In this study, we seed tau pathology in the brains of nontransgenic mice with AD tau and quantify pathology development over 9 months in 134 brain regions. Network modeling of pathology progression shows that diffusion through the connectome is the best predictor of tau pathology patterns. Further, deviations from pure neuroanatomical spread are used to estimate regional vulnerability to tau pathology and identify related gene expression patterns. Last, we show that pathology spread is altered in mice harboring a mutation in leucine-rich repeat kinase 2. While tau pathology spread is still constrained by anatomical connectivity in these mice, it spreads preferentially in a retrograde direction. This study provides a framework for understanding neuropathological progression in tauopathies.

Cognition at Each Stage of Lewy Body Disease with Co-occurring Alzheimer's Disease Pathology.

Background:Alzheimer’s disease neuropathologic change (ADNC) may contribute to dementia in patients with Lewy body disease (LBD) pathology.Objective:To examine how co-occurring ADNC impacts domain specific cognitive impairments at each pathologic stage (brainstem, limbic, cerebral cortical) of LBD.Methods:2,433 participants with antemortem longitudinal neuropsychological assessment and postmortem neuropathological assessment from the National Alzheimer’s Coordinating Center’s Uniform Data Set were characterized based on the evaluation of ADNC and LBD. Longitudinal mixed-models were used to derive measures of cumulative cognitive deficit for each cognitive domain at each pathologic stage of LBD (brainstem, limbic, and cerebral cortical).Results:111 participants with a pathologic diagnosis of LBD, 741 participants with combined LBD and ADNC, 1,357 participants with ADNC only, and 224 with no pathology (healthy controls) were included in the analyses. In the executive/visuospatial domain, combined LBD and ADNC showed worse deficits than LBD only when Lewy bodies were confined to the brainstem, but no difference when Lewy bodies extended to the limbic or cerebral cortical regions. The cerebral cortical LBD only group exhibited greater executive/visuospatial deficits than the ADNC only group. By contrast, the ADNC only group and the combined pathology group both demonstrated significantly greater cumulative memory deficits relative to Lewy body disease only, regardless of stage.Conclusion:The impact of co-occurring ADNC on antemortem cumulative cognitive deficits varies not only by domain but also on the pathological stage of Lewy bodies. Our findings stress the cognitive impact of different patterns of neuropathological progression in Lewy body diseases.

Neuroprotective effect of mitochondrial translocator protein ligand in a mouse model of tauopathy

BackgroundThe translocator protein (TSPO) has been identified as a positron emission tomography (PET)-visible biomarker of inflammation and promising immunotherapeutic target for the treatment of Alzheimer’s disease (AD). While TSPO ligands have been shown to reduce the accumulation of the toxic Alzheimer’s beta-amyloid peptide, their effect on tau pathology has not yet been investigated. To address this, we analyzed the effects of TSPO ligand, Ro5-4864, on the progression of neuropathology in rTg4510 tau transgenic mice (TauTg).MethodsBrain atrophy, tau accumulation, and neuroinflammation were assessed longitudinally using volumetric magnetic resonance imaging, tau-PET, and TSPO-PET, respectively. In vivo neuroimaging results were confirmed by immunohistochemistry for markers of neuronal survival (NeuN), tauopathy (AT8), and inflammation (TSPO, ionized calcium-binding adaptor molecule 1 or IBA-1, and complement component 1q or C1q) in brain sections from scanned mice.ResultsTSPO ligand treatment attenuated brain atrophy and hippocampal neuronal loss in the absence of any detected effect on tau depositions. Atrophy and neuronal loss were strongly associated with in vivo inflammatory signals measured by TSPO-PET, IBA-1, and levels of C1q, a regulator of the complement cascade. In vitro studies confirmed that the TSPO ligand Ro5-4864 reduces C1q expression in a microglial cell line in response to inflammation, reduction of which has been shown in previous studies to protect synapses and neurons in models of tauopathy.ConclusionsThese findings support a protective role for TSPO ligands in tauopathy, reducing neuroinflammation, neurodegeneration, and brain atrophy.

In vivo Characterization of Biochemical Variants of Amyloid-β in Subjects with Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease Neuropathological Change.

Background:Stepwise occurrence of biochemically modified amyloid-β (Aβ) in the brain of subjects with Alzheimer’s disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aβ is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aβ are indeed also suffering from AD.Objective:We assessed the occurrence of biochemically modified Aβ variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia.Methods:We assessed Aβ proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry.Results:The pyroglutamylated Aβ (pyAβ) precedes the aggregation of phosphorylated Aβ (pAβ) during the AD neuropathological change progression; moreover, these modified variants of Aβ correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aβ aggregation that might be of significance for neurodegeneration leading to cognitive impairment.Conclusion:The observation that both pyAβ and pAβ are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aβ in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aβ is observed in the biopsy, the biochemical characterization is of interest.

Molecular and Diffusion Tensor Imaging Biomarkers of Traumatic Brain Injury: Principles for Investigation and Integration.

The last 20 years have seen the advent of new technologies that enhance the diagnosis and prognosis of traumatic brain injury (TBI). There is recognition that TBI affects the brain beyond initial injury, in some cases inciting a progressive neuropathology that leads to chronic impairments. Medical researchers are now searching for biomarkers to detect and monitor this condition. Perhaps the most promising developments are in the biomolecular and neuroimaging domains. Molecular assays can identify proteins indicative of neuronal injury and/or degeneration. Diffusion imaging now allows sensitive evaluations of the brain's cellular microstructure. As the pace of discovery accelerates, it is important to survey the research landscape and identify promising avenues of investigation. In this review, we discuss the potential of molecular and diffusion tensor imaging (DTI) biomarkers in TBI research. Integration of these technologies could advance models of disease prognosis, ultimately improving care. To date, however, few studies have explored relationships between molecular and DTI variables in patients with TBI. Here, we provide a short primer on each technology, review the latest research, and discuss how these biomarkers may be incorporated in future studies.

Thymoquinone Prevents Dopaminergic Neurodegeneration by Attenuating Oxidative Stress Via the Nrf2/ARE Pathway

Studies have indicated that oxidative stress plays a crucial role in the development of Parkinson’s disease (PD) and other neurodegenerative conditions. Research has also revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) triggers the expression of antioxidant genes via a series of antioxidant response elements (AREs), thus preventing oxidative stress. Thymoquinone (TQ) is the bioactive component of Nigella sativa, a medicinal plant that exhibits antioxidant and neuroprotective effects. In the present study we examined whether TQ alleviates in vivo and in vitro neurodegeneration induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by acting as an activator of the Nrf2/ARE cascade. We showed that TQ significantly reduced MPP+-mediated cell death and apoptosis. Moreover, TQ significantly elevated the nuclear translocation of Nrf2 and significantly increased the subsequent expression of antioxidative genes such as Heme oxygenase 1 (HO-1), quinone oxidoreductase (NQO1) and Glutathione-S-Transferase (GST). The application of siRNA to silence Nrf2 led to an abolishment in the protective effects of TQ. We also found that the intraperitoneal injection of TQ into a rodent model of PD ameliorated oxidative stress and effectively mitigated nigrostriatal dopaminergic degeneration by activating the Nrf2-ARE pathway. However, these effects were inhibited by the injection of a lentivirus wrapped Nrf2 siRNA (siNrf2). Collectively, these findings suggest that TQ alleviates progressive dopaminergic neuropathology by activating the Nrf2/ARE signaling cascade and by attenuating oxidative stress, thus demonstrating that TQ is a potential novel drug candidate for the treatment of PD.

Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer's Disease.

There is an extensive literature relating to factors associated with the development of Alzheimer's disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered.

Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson\u2019s disease

Wilson’s disease (WD) is an inherited disorder characterized by excessive accumulation of copper in the body, particularly in the liver and brain. In the central nervous system (CNS), extracellular copper accumulation triggers pathological microglial activation and subsequent neurotoxicity. Growing evidence suggests that levels of inflammatory cytokines are elevated in the brain of murine WD models. However, the mechanisms associated with copper deposition to neuroinflammation have not been completely elucidated. In this study, we investigated how the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome contributes to copper-mediated neuroinflammation in an animal model of WD. Elevated levels of interleukin-1β, interleukin-18, interleukin-6, and tumor necrosis factor-α were observed in the sera of WD patients and toxic milk (TX) mice. The protein levels of inflammasome adaptor molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), cleaved caspase-1, and interleukin-1β were upregulated in the brain regions of the TX mice. The NLRP3 inflammasome was activated in the TX mice brains. Furthermore, the activation of NLRP3 inflammasome was noted in primary microglia treated with CuCl2, accompanied by the increased levels of cleaved caspase-1, ASC, and interleukin-1β. Blocking NLRP3 inflammasome activation with siNlrp3 or MCC950 reduced interleukin-1β and interleukin-18 production, thereby effectively mitigating cognitive decline, locomotor behavior impairment, and neurodegeneration in TX mice. Overall, our study demonstrates the contribution of copper overload-mediated activation of NLRP3 inflammasome to progressive neuropathology in the CNS of a murine model of WD. Therefore, blockade of the NLRP3 inflammasome activation could be a potential therapeutic strategy for WD.

Microglial phenotypes in the brains of aging people with Down syndrome and Alzheimer disease

AbstractBackgroundMicroglial cells play an important role in maintaining normal brain function, but changes in microglia morphology may reflect the functional state of the cell, and potentially contribute to the development and progression of Alzheimer disease (AD). People with Down syndrome (DS) inevitably develop AD neuropathology by 40 years of age, but little is known about microglial phenotypes in this population.MethodsAutopsy tissue from the posterior cingulate cortex (PCC) from six groups were included in the study: DS (<40 years), DS with AD (>40 years), sporadic non‐DS AD and young, middle‐aged and aged non‐DS controls. Sections were stained with the microglia marker Iba1 and scanned with the Aperio ScanScope XT digital slide scanner Five microglia morphological types were assessed: ramified, hypertrophic, dystrophic, rod‐shaped and amoeboid.ResultsAcross all groups, individuals with DS have higher numbers of hypertrophic microglial cells in their white matter. In the gray matter, the numbers of ramified microglial cells declines with age across controls and individuals with DS. Individuals with DSAD had significantly fewer ramified microglia than controls and the younger individuals with DS. Higher numbers of dystrophic microglia were also observed in individuals with DSAD relative to the other groups. Interestingly, individuals with DSAD also exhibited more rod‐shaped and amoeboid cells than the AD group.ConclusionOverall, individuals with DS and DSAD are associated with a microglial phenotype that distinguishes them from non‐DS controls. Our findings suggest a progressive change in microglia patterns over time as people with DS are aging with a trend towards more dystrophic microglial cells. These results reinforce the differences observed in the neuroinflammation phenotype in individuals with DS, and contribute to our understanding of the role that microglia cells play in the development and progression of AD neuropathology and dementia in people with DS.

Genome‐wide DNA methylation signatures of tau and amyloid neuropathology

AbstractBackgroundThe onset and progression of Alzheimer’s disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and the accumulation of β‐amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD, the regulatory genomic mechanisms involved in disease progression are not fully understood. DNA methylation (DNAm) is the most widely studied epigenetic modification in human disease, with recent work by our group robustly linking methylomic variation to AD and other neurodegenerative disorders. To date, no study has systematically profiled DNAm in mouse models of AD. This study aimed to relate progressive changes in DNAm to AD neuropathology in the cortex, using transgenic models of amyloid and tau pathology.MethodWe used transgenic mice harboring human microtubule‐associated protein tau (MAPT, rTg4510) and amyloid precursor protein (APP, J20) mutations to investigate epigenomic and transcriptional changes associated with the development of tau and amyloid pathology. Using sequencing‐based approaches, we quantified changes in DNAm and gene expression identifying genomic signatures paralleling the progression of tau and amyloid across multiple brain regions. Methylomic and transcriptomic changes associated with amyloid and tau pathology were compared to similar data generated from human AD brain.ResultWe identified progressive changes in gene regulation associated with the development of AD neuropathology, including changes in DNA methylation and gene expression at loci previously identified in previous and ongoing human AD studies (Ank1, Hoxa, Abca7, Bin1). Of note, significantly upregulated genes were strikingly enriched for genes involved in immune regulation, and significantly downregulated genes were enriched for synaptic function pathways related to AD. This study represents the most systematic analysis of progressive changes in gene expression and DNA modifications in mouse models of AD pathology and the first to focus specifically on the entorhinal cortex, a key region affected early in human AD.ConclusionOur data provide further evidence for an immune‐response to the accumulation of tau and Aβ, and reveal novel genomic pathways associated with the progression of AD neuropathology.

Mitochondria‐targeted therapeutics restore cognitive function and halt progression of neuropathology in symptomatic AD mice

AbstractBackgroundWe have previously demonstrated that partial reduction of mitochondrial complex I (MCI) activity using small molecules is efficacious in decreasing levels of amyloid beta (Aβ), phosphorylated Tau, augmenting mitochondrial bioenergetics, promoting resistance to oxidative stress and restoring mitochondrial axonal trafficking, levels of BDNF and synaptic proteins in pre‐symptomatic APP/PS1 mice. In parallel, these mice demonstrated an improved cognitive and behavioral phenotype compared to their untreated littermates.MethodIn the current study, we tested whether treatment with MCI inhibitors could halt the disease progression when treatment was administered to symptomatic APP/PS1 mice.ResultTreatment improved glucose tolerance, prevented body weight loss, and ameliorated systemic inflammation. Treatment improved glucose uptake in the brain measured using FDG‐PET imaging. Electrophysiological recording in hippocampus indicated that synaptic activity and LTP were restored in treated APP/PS1 mice. Data gathered using 3D electron microscopy reconstruction of dendrites in CA1 region of hippocampus showed that treatment increased the population of mature dendritic spines in APP/PS1 mice, which correlates with restored synaptic activity and improved glucose uptake and utilization in the brain. Immunohistochemical analysis showed that treated APP/PS1 mice had reduced brain level of Aβ plaques, markers of inflammation and reduced degeneration of TH+ neurons in locus coeruleus. The RNA‐seq gene function enrichment analysis showed that pathways down‐regulated by treatment with MCI inhibitors in APP/PS1 mice included the ones involved in oxidative stress and immune system response. Moreover, RNA‐seq data analysis depicted a cluster of genes involved in dendritic morphology, axonal guidance and neuronal development, which expression were reverted by treatment in APP/PS1 mice to the level observed in NTG mice. Western blot analysis in cortico‐hippocampal brain region of APP/PS1 mice confirmed that treatment increased signaling molecules involved in IGF‐1/insulin pathway, mitochondrial biogenesis, oxidative stress protection, autophagy and synaptic function.ConclusionOverall, our data suggest that long‐term treatment with MCI inhibitors is safe and efficacious in restoring cognitive function and preventing degeneration in symptomatic APP/PS1 mice. Therefore, partial MCI inhibitors represent a promising therapeutic approach to ameliorate AD and promote healthy aging.

Functional alterations in visual networks underlie differences in the phenomenology of visual hallucinations in Lewy body disease

AbstractBackgroundThe phenomenology of visual hallucinations (VH) in Lewy Body Disease (LBD) is heterogenous including minor phenomena (passage, presence, illusions) and complex hallucinations. Underlying mechanisms are largely unknown and here we investigated whether distinct neural networks underpin minor (MVH) and complex VH (CVH).MethodLBD patients (n=17 DLB, n=10 PDD; mean age=76.5±6.5; mean MMSE=20.2±5.7, male=16; 59.2%) with VH underwent resting state fMRI and the North East Visual Hallucinations Interview (NEVHI) to assess the phenomenology, duration and frequency of VH. Using multiple regression models, we performed a seed‐to‐seed functional connectivity (FC) analysis to identify specific nodes associated with i) duration, ii) frequency and iii) severity of MVH (controlling for CVH and MMSE) or CVH (controlling for MVH and MMSE).ResultThe severity, frequency and duration of MVH was negatively associated with FC between early visual areas (EVA) and regions of the ventral visual stream, and positively associated with FC between EVA and regions of the dorsal visual stream that may reflect the phenomenology of passage and presence. Furthermore, the duration of MVH was negatively associated with FC between the brainstem and EVA that may be linked to LBD brainstem neuropathology and positively associated with FC between areas of the dorsal visual stream (Table 1). The severity and duration of CVH was negatively associated with FC between areas of the ventral visual stream and positively associated with FC between lingual gyrus and supramarginal gyrus, within the salience network, that may relate to the complexity of the hallucination content. The frequency of CVH was negatively associated with FC between areas of the default mode network and the salience network (i.e. supramarginal gyrus) that may reflect attentional dysregulation (Table 2).ConclusionFunctional alterations in distinct visual and attentional networks underpin VH in LBD according to their phenomenology, showing a greater involvement of the brainstem and dorsal visual stream for MVH, and of the ventral visual stream and attentional networks for CVH. These findings can be interpreted according to the hodotopic hypothesis of VH (ffytche et al. 2008) and may reflect a link between VH phenomenology and the neuropathological progression of Braak stage (ffytche et al. 2017).

Modeling Parkinson's Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers.

The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.

TRP Channels Regulation of Rho GTPases in Brain Context and Diseases.

Neurological and neuropsychiatric disorders are mediated by several pathophysiological mechanisms, including developmental and degenerative abnormalities caused primarily by disturbances in cell migration, structural plasticity of the synapse, and blood-vessel barrier function. In this context, critical pathways involved in the pathogenesis of these diseases are related to structural, scaffolding, and enzymatic activity-bearing proteins, which participate in Ca2+- and Ras Homologs (Rho) GTPases-mediated signaling. Rho GTPases are GDP/GTP binding proteins that regulate the cytoskeletal structure, cellular protrusion, and migration. These proteins cycle between GTP-bound (active) and GDP-bound (inactive) states due to their intrinsic GTPase activity and their dynamic regulation by GEFs, GAPs, and GDIs. One of the most important upstream inputs that modulate Rho GTPases activity is Ca2+ signaling, positioning ion channels as pivotal molecular entities for Rho GTPases regulation. Multiple non-selective cationic channels belonging to the Transient Receptor Potential (TRP) family participate in cytoskeletal-dependent processes through Ca2+-mediated modulation of Rho GTPases. Moreover, these ion channels have a role in several neuropathological events such as neuronal cell death, brain tumor progression and strokes. Although Rho GTPases-dependent pathways have been extensively studied, how they converge with TRP channels in the development or progression of neuropathologies is poorly understood. Herein, we review recent evidence and insights that link TRP channels activity to downstream Rho GTPase signaling or modulation. Moreover, using the TRIP database, we establish associations between possible mediators of Rho GTPase signaling with TRP ion channels. As such, we propose mechanisms that might explain the TRP-dependent modulation of Rho GTPases as possible pathways participating in the emergence or maintenance of neuropathological conditions.

The MHC class II transactivator modulates seeded alpha-synuclein pathology and dopaminergic neurodegeneration in an in vivo rat model of Parkinson's disease

BackgroundAbnormal folding, aggregation and spreading of alpha-synuclein (αsyn) is a mechanistic hypothesis for the progressive neuropathology in Parkinson's disease (PD). Spread of αsyn between cells is supported by clinical, neuropathological and experimental evidence. It has been proposed that a pro-inflammatory micro-environment in response to αsyn can promote its aggregation. We have previously shown that allelic differences in the major histocompatibility complex class two transactivator (Mhc2ta) gene, located in the VRA4 locus, alter MHCII expression levels, microglial activation and antigen presentation capacity in rats upon human αsyn over-expression. In addition, Mhc2ta regulated dopaminergic neurodegeneration and the extent of motor impairment. The purpose of this study was to determine whether Mhc2ta regulates αsyn aggregation, propagation and dopaminergic pathology in an αsyn pre-formed fibril (PFF)-seeded in vivo model of PD. MethodsThe DA and DA.VRA4 congenic rat strains share background genome but display differential microglial antigen presenting capacity due to different Mhc2ta alleles in the VRA4 locus. PFFs of human αsyn or BSA solution were injected unilaterally to the striatum of DA and DA.VRA4 rats two weeks after ipsilateral administration of recombinant adeno-associated virus (rAAV) vectors carrying human αsyn or GFP to the substantia nigra pars compacta. Behavioural assessment was performed at 2, 5 and 8 weeks while histological evaluation of αsyn pathology, inflammation and neurodegeneration as well as determination of serum cytokine profiles were performed at 8 weeks. ResultsrAAV-mediated expression of human αsyn in nigral dopaminergic neurons combined with striatal PFF administration induced enhanced αsyn pathology in DA.VRA4 compared to DA rats. Mhc2ta thus significantly regulated the seeding, propagation and toxicity of αsyn in vivo. This was reflected in terms of wider extent and anatomical distribution of αsyn inclusions, ranging from striatum to the forebrain, midbrain, hindbrain and cerebellum in DA.VRA4. Compared to DA rats, DA.VRA4 also displayed enhanced motor impairment and dopaminergic neurodegeneration as well as higher levels of the proinflammatory cytokines IL-2 and TNFα in serum. ConclusionsWe conclude that the key regulator of MHCII expression, Mhc2ta, modulates neuroinflammation, αsyn-seeded Lewy-like pathology, dopaminergic neurodegeneration and motor impairment. This makes Mhc2ta and microglial antigen presentation promising therapeutic targets for reducing the progressive neuropathology and clinical manifestations in PD.

Neurotensin receptor 1 agonist provides neuroprotection in pre-diabetic rats.

Exogenous treatment of a neurotensin receptor 1 (NTR1) agonist exerted the neuroprotection in an obese and Alzheimer's model. However, the effects of NTR1 modulation on peripheral/hippocampal impairment and cognitive deficit following sustained HFD consumption are poorly understood. Forty rats received a normal diet (ND) or HFD for 16 weeks. At week 13, the ND group received a vehicle (n = 8). Thirty-two HFD-fed group were randomized into four subgroups (n = 8/subgroup) with a vehicle, 1 mg/kg of NTR1 agonist, 1 mg/kg of NTR antagonist, and combined treatment (NTR1 agonist-NTR antagonist) for 2 weeks, s.c. injection. Then, the cognitive tests and peripheral/hippocampal parameters were determined. Our findings demonstrated that NTR1 activator reversed obesity and attenuated metabolic impairment in pre-diabetic rats. It also alleviated hippocampal pathologies and synaptic dysplasticity, leading to deceleration or prevention of cognitive impairment progression. Therefore, NTR1 activation would be a possible novel therapy to decelerate or prevent progression of neuropathology and cognitive impairment in the pre-diabetes.

Hyperphosphorylation Renders Tau Prone to Aggregate and to Cause Cell Death.

Alzheimer's disease (AD) is a neurodegenerative disorder without a cure or prevention to date. Hyperphosphorylated tau forms the neurofibrillary tangles (NFTs) that correlate well with the progression of cognitive impairments. Animal studies demonstrated the pathogenic role of hyperphosphorylated tau. Understanding how abnormal phosphorylation renders a normal tau prone to form toxic fibrils is key to delineating molecular pathology and to developing efficacious drugs for AD. Production of a tau bearing the disease-relevant hyperphosphorylation and molecular characters is a pivotal step. Here, we report the preparation and characterization of a recombinant hyperphosphorylated tau (p-tau) with strong relevance to disease. P-tau generated by the PIMAX approach resulted in phosphorylation at multiple epitopes linked to the progression of AD neuropathology. In stark contrast to unmodified tau that required an aggregation inducer, and which had minimal effects on cell functions, p-tau formed inducer-free fibrils that triggered a spike of mitochondrial superoxide, induced apoptosis, and caused cell death at sub-micromolar concentrations. P-tau-induced apoptosis was suppressed by inhibitors for reactive oxygen species. Hyperphosphorylation apparently caused rapid formation of a disease-related conformation. In both aggregation and cytotoxicity, p-tau exhibited seeding activities that converted the unmodified tau into a cytotoxic species with an increased propensity for fibrillization. These characters of p-tau are consistent with the emerging view that hyperphosphorylation causes tau to become an aggregation-prone and cytotoxic species that underlies diffusible pathology in AD and other tauopathies. Our results further suggest that p-tau affords a feasible tool for Alzheimer's disease mechanistic and drug discovery studies.

Serum Tau Proteins as Potential Biomarkers for the Assessment of Alzheimer's Disease Progression.

Total tau (t-tau) and phosphorylated tau (p-tau) protein elevations in cerebrospinal fluid (CFS) are well-established hallmarks of Alzheimer’s disease (AD), while the associations of serum t-tau and p-tau levels with AD have been inconsistent across studies. To identify more accessible non-invasive AD biomarkers, we measured serum tau proteins and associations with cognitive function in age-matched controls (AMC, n = 26), mild cognitive impairment group (MCI, n = 30), and mild-AD group (n = 20) according to the Mini-mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Global Deterioration Scale (GDS) scores. Serum t-tau, but not p-tau, was significantly higher in the mild-AD group than AMC subjects (p < 0.05), and there were significant correlations of serum t-tau with MMSE and GDS scores. Receiver operating characteristic (ROC) analysis distinguished mild-AD from AMC subjects with moderate sensitivity and specificity (AUC = 0.675). We speculated that tau proteins in neuronal cell-derived exosomes (NEX) isolated from serum would be more strongly associated with brain tau levels and disease characteristics, as these exosomes can penetrate the blood-brain barrier. Indeed, ELISA and Western blotting indicated that both NEX t-tau and p-tau (S202) were significantly higher in the mild-AD group compared to AMC (p < 0.05) and MCI groups (p < 0.01). In contrast, serum amyloid β (Aβ1–42) was lower in the mild-AD group compared to MCI groups (p < 0.001). During the 4-year follow-up, NEX t-tau and p-tau (S202) levels were correlated with the changes in GDS and MMSE scores. In JNPL3 transgenic (Tg) mice expressing a human tau mutation, t-tau and p-tau expression levels in NEX increased with neuropathological progression, and NEX tau was correlated with tau in brain tissue exosomes (tEX), suggesting that tau proteins reach the circulation via exosomes. Taken together, our data suggest that serum tau proteins, especially NEX tau proteins, are useful biomarkers for monitoring AD progression.