Differences in Tau Seeding in Newborn and Adult Wild-Type Mice.

Alzheimer's disease (AD) and other tauopathies are common neurodegenerative diseases in older adults; in contrast, abnormal tau deposition in neurons and glial cells occurs only exceptionally in children. Sarkosyl-insoluble fractions from sporadic AD (sAD) containing paired helical filaments (PHFs) were inoculated unilaterally into the thalamus in newborn and three-month-old wild-type C57BL/6 mice, which were killed at different intervals from 24 h to six months after inoculation. Tau-positive cells were scanty and practically disappeared at three months in mice inoculated at the age of a newborn. In contrast, large numbers of tau-positive cells, including neurons and oligodendrocytes, were found in the thalamus of mice inoculated at three months and killed at the ages of six months and nine months. Mice inoculated at the age of newborn and re-inoculated at the age of three months showed similar numbers and distribution of positive cells in the thalamus at six months and nine months. This study shows that (a) differences in tau seeding between newborn and young adults may be related to the ratios between 3Rtau and 4Rtau, and the shift to 4Rtau predominance in adults, together with the immaturity of connections in newborn mice, and (b) intracerebral inoculation of sAD PHFs in newborn mice does not protect from tau seeding following intracerebral inoculation of sAD PHFs in young/adult mice.

Relevance of host tau in tau seeding and spreading in tauopathies.

Human tau seeding and spreading occur following intracerebral inoculation of brain homogenates obtained from tauopathies in transgenic mice expressing natural or mutant tau, and in wild-type (WT) mice. The present study was geared to learning about the patterns of tau seeding, the cells involved and the characteristics of tau following intracerebral inoculation of homogenates from primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), aging-related tau astrogliopathy (ARTAG: astrocytic 4Rtau) and globular glial tauopathy (GGT: 4Rtau with neuronal deposits and specific tau inclusions in astrocytes and oligodendrocytes). For this purpose, young and adult WT mice were inoculated unilaterally in the hippocampus or in the lateral corpus callosum with sarkosyl-insoluble fractions from PART, ARTAG and GGT cases, and were killed at variable periods of three to seven months. Brains were processed for immunohistochemistry in paraffin sections. Tau seeding occurred in the ipsilateral hippocampus and corpus callosum and spread to the septal nuclei, periventricular hypothalamus and contralateral corpus callosum, respectively. Tau deposits were mainly found in neurons, oligodendrocytes and threads; the deposits were diffuse or granular, composed of phosphorylated tau, tau with abnormal conformation and 3Rtau and 4Rtau independently of the type of tauopathy. Truncated tau at the aspartic acid 421 and ubiquitination were absent. Tau deposits had the characteristics of pre-tangles. A percentage of intracellular tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2. Present study shows that seeding and spreading of human tau into the brain of WT mice involves neurons and glial cells, mainly oligodendrocytes, thereby supporting the idea of a primary role of oligodendrogliopathy, together with neuronopathy, in the progression of tauopathies. In addition, it suggests that human tau inoculation modifies murine tau metabolism with the production and deposition of 3Rtau and 4Rtau, and by activation of specific tau kinases in affected cells.

Neuroinflammation in the dorsolateral prefrontal cortex in elderly chronic schizophrenia.

Cognitive deterioration and symptom progression occur in schizophrenia over the course of the disorder. A dysfunction of the immune system/neuroinflammatory pathways has been linked to schizophrenia (SZ). These altered processes in the dorsolateral prefrontal cortex (DLPFC) could contribute to the worsening of the deficits. However, limited studies are available in this brain region in elderly population with long-term treatments. In this study, we explore the possible deregulation of 21 key genes involved in immune homeostasis, including pro- and anti-inflammatory cytokines, cytokine modulators (toll-like receptors, colony-stimulating factors, and members of the complement system) and microglial and astroglial markers in the DLPFC in elderly chronic schizophrenia. We used quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR) on extracts from postmortem DLPFC of elderly subjects with chronic SZ (n = 14) compared to healthy control individuals (n = 14). We report that CSF1R, TLR4, IL6, TNFα, TNFRSF1A, IL10, IL10RA, IL10RB, and CD68 were down-regulated in elderly SZ subjects. Moreover, we found that the expression levels of all the altered inflammatory genes in SZ correlated with the microglial marker CD68. However, no associations were found with the astroglial marker GFAP. This study reveals a decrease in the gene expression of cytokines and immune response/inflammation mediators in the DLPFC of elderly subjects with chronic schizophrenia, supporting the idea of a dysfunction of these processes in aged patients and its possible relationship with active microglia abundance. These findings include elements that might contribute to the cognitive decline and symptom progression linked to DLPFC functioning at advanced stages of the disease.

Dementia with Lewy Bodies: Molecular Pathology in the Frontal Cortex in Typical and Rapidly Progressive Forms.

OBJECTIVES: The goal of this study was to assess mitochondrial function, energy, and purine metabolism, protein synthesis machinery from the nucleolus to the ribosome, inflammation, and expression of newly identified ectopic olfactory receptors (ORs) and taste receptors (TASRs) in the frontal cortex of typical cases of dementia with Lewy bodies (DLB) and cases with rapid clinical course (rpDLB: 2 years or less) compared with middle-aged non-affected individuals, in order to learn about the biochemical abnormalities underlying Lewy body pathology. METHODS: Real-time quantitative PCR, mitochondrial enzymatic assays, and analysis of ß-amyloid, tau, and synuclein species were used. RESULTS: The main alterations in DLB and rpDLB, which are more marked in the rapidly progressive forms, include (i) deregulated expression of several mRNAs and proteins of mitochondrial subunits, and reduced activity of complexes I, II, III, and IV of the mitochondrial respiratory chain; (ii) reduced expression of selected molecules involved in energy metabolism and increased expression of enzymes involved in purine metabolism; (iii) abnormal expression of nucleolar proteins, rRNA18S, genes encoding ribosomal proteins, and initiation factors of the transcription at the ribosome; (iv) discrete inflammation; and (v) marked deregulation of brain ORs and TASRs, respectively. Severe mitochondrial dysfunction involving activity of four complexes, minimal inflammatory responses, and dramatic altered expression of ORs and TASRs discriminate DLB from Alzheimer's disease. Altered solubility and aggregation of α-synuclein, increased ß-amyloid bound to membranes, and absence of soluble tau oligomers are common in DLB and rpDLB. Low levels of soluble ß-amyloid are found in DLB. However, increased soluble ß-amyloid 1-40 and ß-amyloid 1-42, and increased TNFα mRNA and protein expression, distinguish rpDLB. CONCLUSION: Molecular alterations in frontal cortex in DLB involve key biochemical pathways such as mitochondria and energy metabolism, protein synthesis, purine metabolism, among others and are accompanied by discrete innate inflammatory response.

Regional Gene Expression of Inflammation and Oxidative Stress Responses Does Not Predict Neurodegeneration in Aging.

Brain aging is accompanied by increased oxidative stress and what has been termed "neuroinflammation," which might contribute to age-related neurodegenerative diseases. We analyzed expression in the transcription of innate inflammatory response genes in eleven representative regions including frontal, parietal, inferior temporal, cingulate, occipital, entorhinal cortex, caudate, putamen, thalamus, substantia nigra, and cerebellar vermis in aging human brains. We probed members of the complement system, colony stimulating factor receptors, toll-like receptors, and pro- and anti-inflammatory cytokines in the brains of subjects with no neurological disease and neurofibrillary tangles (mean age: 47.1 ± 5.7 years) and those with no neurological disease and neurofibrillary pathology stages I-II (mean age: 70.6 ± 6.3 years). Although the entorhinal and frontal cortex were most altered, gene regulation patterns did not match regions with increased vulnerability. Analysis of false discovery rate thresholds revealed no differences for any gene in any region between the 2 groups, including cases in which individual comparisons analyzed using Student t or nonparametric tests showed apparent differences between groups. Moreover, gene expression of major anti-oxidative stress responses did not match neuroinflammation in aging or increased regional susceptibility to major neurodegenerative diseases.

DNA Methylation Profiles of Selected Pro-Inflammatory Cytokines in Alzheimer Disease.

By means of functional genomics analysis, we recently described the mRNA expression profiles of various genes involved in the neuroinflammatory response in the brains of subjects with late-onset Alzheimer Disease (LOAD). Some of these genes, namely interleukin (IL)-1ß and IL-6, showed distinct expression profiles with peak expression during the first stages of the disease and control-like levels at later stages. IL-1ß and IL-6 genes are modulated by DNA methylation in different chronic and degenerative diseases; it is also well known that LOAD may have an epigenetic basis. Indeed, we and others have previously reported gene-specific DNA methylation alterations in LOAD and in related animal models. Based on these data, we studied the DNA methylation profiles, at single cytosine resolution, of IL-1ß and IL-6 5'-flanking region by bisulphite modification in the cortex of healthy controls and LOAD patients at 2 different disease stages: Braak I-II/A and Braak V-VI/C. Our analysis provides evidence that neuroinflammation in LOAD is associated with (and possibly mediated by) epigenetic modifications.

Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models.

Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a -/- (laforin knock-out) and Epm2b -/- (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 messenger RNAs (mRNAs) are significantly increased in Epm2a -/- mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα, and Il10ra mRNAs are significantly upregulated in Epm2b -/- at the same age. This is accompanied by increased protein levels of IL1-ß, IL6, TNFα, and Cox2 particularly in Epm2b -/- mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b -/- mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.

FOXP2 Expression in Frontotemporal Lobar Degeneration-Tau.

FOXP2 is altered in a variety of language disorders. We found reduced mRNA and protein expression of FOXP2 in frontal cortex area 8 in Pick's disease, and frontotemporal lobar degeneration-tau linked to P301L mutation presenting with language impairment in comparison with age-matched controls and cases with parkinsonian variant progressive supranuclear palsy. Foxp2 mRNA and protein are also reduced with disease progression in the somatosensory cortex in transgenic mice bearing the P301S mutation in MAPT when compared with wild-type littermates. Our findings support the presence of FOXP2 expression abnormalities in sporadic and familial frontotemporal degeneration tauopathies.

Potential Role of Aminoprocalcitonin in the Pathogenesis of Alzheimer Disease.

Increasing evidence suggests that inflammatory responses cause brain atrophy and play a prominent and early role in the progression of Alzheimer disease. Recent findings show that the neuroendocrine peptide aminoprocalcitonin (NPCT) plays a critical role in the development of systemic inflammatory response; however, the presence, possible function, regulation, and mechanisms by which NPCT may be involved in Alzheimer disease neuropathology remain unknown. We explored the expression of NPCT and its interaction with amyloid-ß (Aß), and proinflammatory and neurogenic effects. By using brain samples of Alzheimer disease patients and APP/PS1 transgenic mice, we evaluated the potential role of NPCT on Aß-related pathology. We found that NPCT is expressed in hippocampal and cortical neurons and Aß-induced up-regulation of NPCT expression. Peripherally administered antibodies against NPCT decreased microglial activation, decreased circulating levels of proinflammatory cytokines, and prevented Aß-induced neurotoxicity in experimental models of Alzheimer disease. Remarkably, anti-NPTC therapy resulted in a significant improvement in the behavioral status of APP/PS1 mice. Our results indicate a central role of NPCT in Alzheimer disease pathogenesis and suggest NPCT as a potential biomarker and therapeutic target.

Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies.

Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD) and sporadic Parkinson's disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick's disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression.

Limited Unfolded Protein Response and Inflammation in Neuroserpinopathy.

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare disease characterized by the deposition of multiple intracytoplasmic neuronal inclusions that contain mutated neuroserpin. Tg-Syracuse (Tg-Syr) mice express Ser49Pro mutated neuroserpin and develop clinical and neuropathological features of human FENIB. We used 8-, 34-, 45- and 80-week-old Tg-Syr mice to characterize neuroinflammation and the unfolded protein response (UPR) in a neurodegenerative disease in which abnormal protein aggregates accumulate within the endoplasmic reticulum (ER). There were scattered neuroserpin inclusions in Tg-Syr mice at 8 weeks of age; the numbers of neurons involved and the amount of neuroserpin per neuron increased with age throughout the CNS to 80 weeks of age; no similar inclusions were found in wild type (Tg-WT) mice at any age. Increases in numbers of astrocytes and microglia occurred at advanced disease stages. Among 22 markers in 80-week-old Tg-Syr mice, only II1b and II10rb mRNAs in the somatosensory cortex and CxCl10 and Il10rb mRNAs in the olfactory bulb were upregulated when compared with Tg-WT mice indicating a limited relationship between neuroserpin inclusions and inflammatory responses. The changes were accompanied by a transient increase in expression of Xbp1 spliced at 45 weeks and increased ERdJ4 mRNAs at 80 weeks. The sequestration of UPR activators GRP78 and GRP94 in neuroserpin inclusions might explain the limited UPR responses despite the accumulation of neuroserpin in the ER in this FENIB mouse model.

Neuroinflammatory Gene Regulation, Mitochondrial Function, Oxidative Stress, and Brain Lipid Modifications With Disease Progression in Tau P301S Transgenic Mice as a Model of Frontotemporal Lobar Degeneration-Tau.

Tau P301S transgenic mice (PS19 line) are used as a model of frontotemporal lobar degeneration (FTLD)-tau. Behavioral alterations in these mice begin at approximately 4 months of age. We analyzed molecular changes related to disease progression in these mice. Hyperphosphorylated 4Rtau increased in neurons from 1 month of age in entorhinal and piriform cortices to the neocortex and other regions. A small percentage of neurons developed an abnormal tau conformation, tau truncation, and ubiquitination only at 9/10 months of age. Astrocytosis, microgliosis, and increased inflammatory cytokine and immune mediator expression also occurred at this late stage; hippocampi were the most markedly affected. Altered mitochondrial function, increased reactive oxygen species production, and limited protein oxidative damage were observed in advanced disease. Tau oligomers were only present in P301S mice, they were found in somatosensory cortex and hippocampi at the age of 3 months, and they increased across time in the somatosensory cortex and were higher and sustained in hippocampi. Age-related modifications in lipid composition occurred in both P301S and wild-type mice with regional and phenotypic differences; however, changes of total lipids did not seem to have pathogenic implications. Apoptosis only occurred in restricted regions in late disease. The complex tau pathology, mitochondrial alterations, oxidative stress damage, glial reactions, neuroinflammation, and cell death in P301S mice likely parallel those in FTLD-tau. Thus, therapies should focus first on abnormal tau rather than secondary events that appear late in the course of FTLD-tau.

Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies.

We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as ß-amyloid (Aß)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aß42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.

Neuroinflammatory signals in Alzheimer disease and APP/PS1 transgenic mice: correlations with plaques, tangles, and oligomeric species.

To understand neuroinflammation-related gene regulation during normal aging and in sporadic Alzheimer disease (sAD), we performed functional genomics analysis and analyzed messenger RNA (mRNA) expression by quantitative reverse transcription-polymerase chain reaction of 22 genes involved in neuroinflammation-like responses in the cerebral cortex of wild-type and APP/PS1 transgenic mice. For direct comparisons, mRNA expression of 18 of the same genes was then analyzed in the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 of middle-aged human subjects lacking Alzheimer disease-related pathology and in older subjects with sAD pathology covering Stages I-II/0(A), III-IV/A-B, and V-VI/C of Braak and Braak classification. Modifications of cytokine and immune mediator mRNA expression were found with normal aging in wild-type mice and in middle-aged individuals and patients with early stages of sAD-related pathology; these were accompanied by increased protein expression of certain mediators in ramified microglia. In APP/PS1 mice, inflammatory changes coincided with ß-amyloid (Aß) deposition; increased levels of soluble oligomers paralleled the modified mRNA expression of cytokines and mediators in wild-type mice. In patients with sAD, regulation was stage- and region-dependent and not merely acceleration and exacerbation of mRNA regulation with aging. Gene regulation at first stages of AD was not related to hyperphosphorylated tau deposition in neurofibrillary tangles, Aß plaque burden, concentration of Aß1-40 (Aß40) and Aß1-42 (Aß42), or fibrillar Aß linked to membranes but rather to increased levels of soluble oligomers. Thus, species differences and region- and stage-dependent inflammatory responses in sAD, particularly at the initial stages, indicate the need to identify new anti-inflammatory compounds with specific molecular therapeutic targets.

Subtype and regional-specific neuroinflammation in sporadic creutzfeldt-jakob disease.

The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 and VV2 subtypes compared to age-matched controls. Deregulated genes include pro- and anti-inflammatory cytokines, toll-like receptors, colony stimulating factors, cathepsins, members of the complement system, and members of the integrin and CTL/CTLD family with particular regional and sCJD subtype patterns. Analysis of cytokines and mediators at protein level shows expression of selected molecules and receptors in neurons, in astrocytes, and/or in microglia, thus suggesting interactions between neurons and glial cells, mainly microglia, in the neuroinflammatory response in sCJD. Similar inflammatory responses have been shown in the tg340 sCJD MM1 mice, revealing a progressive deregulation of inflammatory mediators with disease progression. Yet, inflammatory molecules involved are subjected to species differences in humans and mice. Moreover, inflammatory-related cell signaling pathways NFκB/IKK and JAK/STAT are activated in sCJD and sCJD MM1 mice. Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD. Considering this scenario, measures tailored to modulate (activate or inhibit) specific molecules could be therapeutic options in CJD.

αB-crystallin and HSP27 in glial cells in tauopathies.

Tauopathies are neurodegenerative diseases characterized by hyper-phosphorylated tau deposition in neurons and glial cells. Chaperones, such as small heat shock proteins αB-crystallin and HSP27 highly expressed in normal glial cells, have been postulated as putative molecules preventing abnormal deposition and folding in glial cells in tauopathies. The objective of this work was to assess the expression of αB-crystallin, phosphorylated αB-crystallin at Ser59 and HSP27 in glial cells with and without tau deposits in progressive supranuclear palsy, corticobasal degeneration (CBD), argyrophilic grain disease (AGD), Pick's disease (PiD), Alzheimer's disease, frontotemporal lobar degeneration associated with mutations in the tau gene (FTLD-tau), globular glial tauopathy (GGT) and tauopathy in the elderly. Immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy have been used for this purpose. Increased expression of αB-crystallin and phosphorylated αB-crystallin at Ser59 occurs in a subpopulation of glial cells with and without hyper-phosphorylated tau deposition in all the analyzed tauopathies, but their expression in neurons is restricted to ballooned neurons in CBD, AGD and PiD. HSP27 barely co-localizes with tau and with phosphorylated αB-crystallin at Ser59, thus making the formation of active dimers operating as chaperones unlikely. Results suggest a limited function of αB-crystallin and HSP27 in preventing abnormal tau protein deposition in glial cells and neurons; in addition, the expression of αB-crystallin phosphorylated at Ser59 may act as a protective factor in glial cells.

Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression.

Tauopathies are degenerative diseases characterized by the accumulation of phosphorylated tau in neurons and glial cells. With some exceptions, tau deposits in neurons are mainly manifested as pretangles and tangles unrelated to the tauopathy. It is thought that abnormal tau deposition in neurons occurs following specific steps, but little is known about the progression of tau pathology in glial cells in tauopathies. We compared tau pathology in different astrocyte phenotypes and oligodendroglial inclusions with that in neurons in a large series of tauopathies, including progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick disease, frontotemporal lobar degenerations (FTLD) associated with mutations in the tau gene, globular glial tauopathy (GGT), and tauopathy in the elderly. Our findings indicate that disease-specific astroglial phenotypes depend on i) the primary amino acid sequence of tau (mutated tau, 3Rtau, and 4Rtau); ii) phospho-specific sites of tau phosphorylation, tau conformation, tau truncation, and ubiquitination in that order (which parallel tau modifications related to pretangle and tangle stages in neurons); and iii) modifications of the astroglial cytoskeleton. In contrast to astrocytes, coiled bodies in oligodendrocytes have similar characteristics whatever the tauopathy, except glial globular inclusions in GGT, and coiled bodies and globular oligodendroglial inclusions in FTLD-tau/K317M. These observations indicate that tau pathology in glial cells largely parallels, but is not identical to, that in neurons in many tauopathies.

PrP mRNA and protein expression in brain and PrP(c) in CSF in Creutzfeldt-Jakob disease MM1 and VV2.

Creutzfeldt-Jakob disease (CJD) is a heterogenic neurodegenerative disorder associated with abnormal post-translational processing of cellular prion protein (PrP(c)). CJD displays distinctive clinical and pathological features which correlate with the genotype at the codon 129 (methionine or valine: M or V respectively) in the prion protein gene and with size of the protease-resistant core of the abnormal prion protein PrP(sc) (type 1: 20/21 kDa and type 2: 19 kDa). MM1 and VV2 are the most common sporadic CJD (sCJD) subtypes. PrP mRNA expression levels in the frontal cortex and cerebellum are reduced in sCJD in a form subtype-dependent. Total PrP protein levels and PrP(sc) levels in the frontal cortex and cerebellum accumulate differentially in sCJD MM1 and sCJD VV2 with no relation between PrP(sc) deposition and spongiform degeneration and neuron loss, but with microgliosis, and IL6 and TNF-α response. In the CSF, reduced PrP(c), the only form present in this compartment, occurs in sCJD MM1 and VV2. PrP mRNA expression is also reduced in the frontal cortex in advanced stages of Alzheimer disease, Lewy body disease, progressive supranuclear palsy, and frontotemporal lobe degeneration, but PrP(c) levels in brain varies from one disease to another. Reduced PrP(c) levels in CSF correlate with PrP mRNA expression in brain, which in turn reflects severity of degeneration in sCJD.

Characterization of thorn-shaped astrocytes in white matter of temporal lobe in Alzheimer's disease brains.

Thorn-shaped astrocytes (TsA) are mainly localized in the periventricular white matter of the temporal lobe in a subgroup of aged individuals usually in the context of Alzheimer's disease (AD). Immunohistochemistry of TsA shows 4Rtau deposition, tau phosphorylation at different sites recognized with phosphospecific anti-tau antibodies Thr181, Ser202, Ser214, Thr231, Ser396, Ser422, and clones AT8 and PHF-1, and conformational changes revealed with Alz50 and MC-1 antibodies; TsA are also immunostained with antibodies to active tau kinases MAPK/ERK-P, SAPK/JNK-P, p38-P and GSK-3ß. These findings are common to neurofibrillary tangles in AD. However, TsA are not stained with 3Rtau antibodies, and they are seldom stained or not at all with phosphospecific tauSer262 and with Tau-C3 antibody, which recognizes the latter tau truncation at aspartic acid 421. Previous studies have shown that tau phosphorylation at Ser262 reduces tau binding to microtubules and increases caspase-3 activity, whereas tau truncation at aspartic acid 421 is associated with tau ubiquitination, and toxic effects of tau. In this line, ubiquitin is not accumulated in TsA, and in situ end-labeling of nuclear DNA fragmentation shows absence of degeneration in TsA. These observations support the concept that tau lesions in neurons differ from those seen in TsA in AD.

Venezuelan equine encephalitis virus activity in the Gulf Coast region of Mexico, 2003-2010.

Venezuelan equine encephalitis virus (VEEV) has been the causative agent for sporadic epidemics and equine epizootics throughout the Americas since the 1930s. In 1969, an outbreak of Venezuelan equine encephalitis (VEE) spread rapidly from Guatemala and through the Gulf Coast region of Mexico, reaching Texas in 1971. Since this outbreak, there have been very few studies to determine the northward extent of endemic VEEV in this region. This study reports the findings of serologic surveillance in the Gulf Coast region of Mexico from 2003-2010. Phylogenetic analysis was also performed on viral isolates from this region to determine whether there have been substantial genetic changes in VEEV since the 1960s. Based on the findings of this study, the Gulf Coast lineage of subtype IE VEEV continues to actively circulate in this region of Mexico and appears to be responsible for infection of humans and animals throughout this region, including the northern State of Tamaulipas, which borders Texas.