H2 inhalation therapy in patients with moderate COVID-19 (H2COVID): a prospective ascending-dose phase I clinical trial.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has triggered a serious global health crisis, resulting in millions of reported deaths since its initial identification in China in November 2019. The global disparities in immunization access emphasize the urgent need for ongoing research into therapeutic interventions. This study focuses on the potential use of molecular dihydrogen (H2) inhalation as an adjunctive treatment for COVID-19. H2 therapy shows promise in inhibiting intracellular signaling pathways associated with inflammation, particularly when administered early in conjunction with nasal oxygen therapy. This phase I study, characterized by an open-label, prospective, monocentric, and single ascending-dose design, seeks to assess the safety and tolerability of the procedure in individuals with confirmed SARS-CoV-2 infection. Employing a 3 + 3 design, the study includes three exposure durations (target durations): 1 day (D1), 3 days (D2), and 6 days (D3). We concluded that the maximum tolerated duration is at least 3 days. Every patient showed clinical improvement and excellent tolerance to H2 therapy. To the best of our knowledge, this phase I clinical trial is the first to establish the safety of inhaling a mixture of H2 (3.6%) and N2 (96.4%) in hospitalized COVID-19 patients. The original device and method employed ensure the absence of explosion risk. The encouraging outcomes observed in the 12 patients included in the study justify further exploration through larger, controlled clinical trials. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04633980.

Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in male mouse models.

Neurofibrillary tangles (NFT), a neuronal lesion found in Alzheimer's disease (AD), are composed of fibrillary aggregates of modified forms of tau proteins. The propagation of NFT follows neuroanatomical pathways suggesting that synaptically connected neurons could transmit tau pathology by the recruitment of normal tau in a prion-like manner. Moreover, the intracerebral injection of pathological tau from AD brains induces the seeding of normal tau in mouse brain. Creutzfeldt-Jacob disease has been transmitted after ocular transplants of cornea or sclera and the scrapie agent can spread across the retino-tectal pathway after intraocular injection of scrapie mouse brain homogenates. In AD, a tau pathology has been detected in the retina. To investigate the potential risk of tau pathology transmission during eye surgery using AD tissue material, we have analysed the development of tau pathology in the visual pathway of mice models expressing murine tau, wild-type or mutant human tau after intraocular injection of pathological tau proteins from AD brains. Although these pathological tau proteins were internalized in retinal ganglion cells, they did not induce aggregation of endogenous tau nor propagation of a tau pathology in the retino-tectal pathway after a 6-month incubation period. These results suggest that retinal ganglion cells exhibit a resistance to develop a tau pathology, and that eye surgery is not a major iatrogenic risk of transmission of tau pathology, contrary to what has been observed for transmission of infectious prions in prion diseases.

Clinical, functional and genetic characterization of 16 patients suffering from chronic granulomatous disease variants - identification of 11 novel mutations in CYBB.

Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910 , X91- or X91+ ), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910 -CGD and two X91- -CGD). One X910 -CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91- -CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91- -CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91- -CGD patients correlates with mild clinical forms of CGD, whereas X910 -CGD and X91+ -CGD cases remain the most clinically severe forms.

Clusterin regulates ß-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway.

Although the mechanism of Aß action in the pathogenesis of Alzheimer's disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aß neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aß/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aß toxicity and DKK1 upregulation and, conversely, Aß increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1. To further elucidate how the clusterin-dependent induction of Dkk1 by Aß mediates neurotoxicity, we measured the effects of Aß and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt-planar cell polarity (PCP)-c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aß neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aß-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt-PCP-JNK pathway is active in an Aß-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aß induces a clusterin/p53/Dkk1/wnt-PCP-JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aß in neurodegenerative diseases.

Pneumocystis jirovecii (Pj) quantitative PCR to differentiate Pj pneumonia from Pj colonization in immunocompromised patients.

Conventional polymerase chain reaction (PCR) in respiratory samples does not differentiate between Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii (Pj) colonization. We used Pj real-time quantitative PCR (qPCR) with the objective to discriminate PCP from Pj colonization in immunocompromised patients. All positive Pj qPCR [targeting the major surface glycoprotein (MSG) gene] obtained in respiratory samples from immunocompromised patients presenting pneumonia at the Grenoble University Hospital, France, were collected between August 2009 and April 2011. Diagnoses were retrospectively determined by a multidisciplinary group of experts blinded to the Pj qPCR results. Thirty-one bronchoalveolar lavages and four broncho aspirations positive for the Pj qPCR were obtained from 35 immunocompromised patients. Diagnoses of definite, probable, and possible PCP, and pneumonia from another etiology were retrospectively made for 7, 4, 5, and 19 patients, respectively. Copy numbers were significantly higher in the "definite group" (median 465,000 copies/ml) than in the "probable group" (median 38,600 copies/ml), the "possible group" (median 1,032 copies/ml), and the "other diagnosis group" (median 390 copies/ml). With the value of 3,160 copies/ml, the sensitivity and specificity of qPCR for the diagnosis of PCP were 100 % and 70 %, respectively. With the value of 31,600 copies/ml, the sensitivity and specificity were 80 % and 100 %, respectively. The positive predictive value was 100 % for results with more than 31,600 copies/ml and the negative predictive value was 100 % for results with fewer than 3,160 copies/ml. qPCR targeting the MSG gene can be helpful to discriminate PCP from Pj colonization in immunocompromised patients, using two cut-off values, with a gray zone between them.

Subacute tuberculous otitis media complicated by petrositis and meningitis.

AIMS: The aim of our case study is to illustrate diagnostic and therapeutic difficulties as well as gravity related to tuberculous otitis media with intracranial complications. CASE PRESENTATION: A diabetic male patient of 65 years old was treated for subacute otitis media with mixed hearing loss. Early bacteriologic samples from ear exudates revealed opportunistic pathogens. Clinical evolution after four months was marked by the appearance of mastoiditis with facial paralysis. The patient presented petrositis and bilateral laryngeal paralysis with lymphocytic meningitis after six and eight months respectively. Tuberculosis was suspected after a positive ELlspot tests with appearance of biologic markers of hepatic dysfunction like cholestasis and hepatic cytolysis. Although antituberculous treatment was instaured even without isolation of acid fast bacilli, the patient died after ten months. CONCLUSION: Subacute otitis media complicated by labyrinthitis, early onset of facial paralysis or any other oranial nerve palsy should raise suspicion of tuberculosis. The prognosis depends on early diagnosis which remains difficult despite morphological and metabolic imaging. The diagnostic workup should include histological and bacteriologic samples, liver markers of intacellular damage as well as ELlspot test. The prognosis remains poor especially in immunocompromised patients despite appropriate treatment.

Lactobacillus bacteremia: Pathogen or prognostic marker?

OBJECTIVE: Lactobacillus bacteremia is a rare event and its epidemiology is poorly known. Whether Lactobacillus bacteremia is a contaminant, a risk factor, or a risk marker of death remains an open question. PATIENTS AND METHODS: We conducted a retrospective study of patients presenting with Lactobacillus bacteremia (LB), between January 2005 and December 2014, at the Grenoble University Hospital. RESULTS: LB was observed in 38 patients (0.34% of all positive blood cultures). Cancer (40%), immunosuppression (37%), and use of central venous devices (29%) were frequently associated with LB. We observed a significant increase with time in the number of Lactobacillus positive blood cultures among all blood cultures performed (P=0.04). LBs were divided into two clinical-biological presentations: secondary bacteremia with a known portal of entry (n=30) and isolated bacteremia (n=8). Case fatality was 31% at D28, 55.2% at 1 year in the secondary bacteremia group, and 12.5% (both at D28 and 1 year) in the isolated bacteremia group. Secondary bacteremia with a known portal of entry was significantly associated with case fatality after adjustment for age, co-infection, cancer, immunosuppression, diabetes, and sex (OR 14.9 [1.04-216] P=0.047) for fatality at one year, but not for D28 fatality (P=0.14). CONCLUSION: Lactobacillus bacteremia may be an important marker of disease severity rather than a pathogen, suggesting comorbidities. It should not be considered a contaminant, but should lead physicians to screen for associated infections and underlying diseases.

A multicentre, prospective, non-randomized, sequential, open-label trial to demonstrate the bioequivalence between intravenous immunoglobulin new generation (IGNG) and standard IV immunoglobulin (IVIG) in adult patients with primary immunodeficiency (PID).

OBJECTIVES: To demonstrate the bioequivalence between 2 intravenous immunoglobulin (IVIG) preparations, TEGELINE® and ClairYg®, a ready-to-use 5% IVIG, in primary immunodeficiency (PID). Secondary objectives were to assess the efficacy, safety and pharmacokinetics of ClairYg®. METHODS: Twenty-two adult PID patients receiving stable doses of TEGELINE® (5% lyophilized IVIG) were switched to ClairYg® for 6 months. ClairYg® was administered under the same conditions as TEGELINE®, either every 3 or 4 weeks. The primary endpoint was mean average total IgG trough level at steady state with ClairYg® versus TEGELINE®. Clinical efficacy was also assessed in terms of infections and associated events. RESULTS: Bioequivalence was established with a mean average total IgG trough level at steady state being 8.05g/L with TEGELINE® and 9.17g/L with ClairYg® (i.e. geometric mean for the difference between ClairYg® and TEGELINE® was 1.136; [90% CI: 1.092-1.181] P<0.001), within the pre-specified margin to establish bioequivalence (0.80-1.25). Total IgG trough levels remained clinically adequate (>4-6g/L) throughout the study. No patient was hospitalized for infection or had serious bacterial infections while receiving ClairYg®. The median annualized infections rate per patient was similar for both products: 4.35 [0; 21.8] for TEGELINE® and 4.30 [0; 15.1] for ClairYg®. Infections were less common with higher IgG trough levels (>8.16g/L). ClairYg® showed good safety, in particular good hepatic and renal tolerance, and did not induce hemolysis. ClairYg® pharmacokinetics profile was comparable to that of TEGELINE®. CONCLUSION: ClairYg® is safe and effective in the treatment of adult PID.

The changing pattern of Fusobacterium infections in humans: recent experience with Fusobacterium bacteraemia.

A retrospective study was conducted of 26 adult cases of fusobacterium bacteraemia that occurred between 1998 and 2003 at Center Hospitalier Universitaire de Grenoble, France. Most patients presented with pre-existing adverse medical conditions, including evolving malignant diseases (eight patients), recent surgery (four patients), and chronic organ failure (six patients). Only one patient presented with a classic Lemierre's syndrome. These results suggest an opportunistic pattern of modern fusobacterium infections.

Hospital-wide prospective mandatory surveillance of invasive aspergillosis in a French teaching hospital (2000-2002).

A multidisciplinary working group devoted to epidemiological surveillance of invasive aspergillosis (IA) was created in January 2000 in Grenoble University Hospital. This article presents the results of a three-year IA surveillance. The multidisciplinary working group surveyed all hospitalized patients, and the mycology laboratory detected most suspected IA cases. Cases were reviewed monthly by the Aspergillosis Committee, and were classified according to international consensus criteria. Possible nosocomial acquisition was determined. Among the 490 alerts, 74 IA cases were observed: six proven cases (8%), 36 (49%) probable cases and 32 (43%) possible cases. The incidence was 4.4 (95% CI 3.4-5.4) IA/100 000 patient-days. Among the proven and probable IA cases, we observed 10 nosocomial cases and six cases of undetermined origin. No cases were noted in the protected rooms in the haematology unit. Only one cluster of cases (three nosocomial cases) was detected in the haematology unit. Forty-three percent of cases (N=32) were hospitalized in the haematology unit, and all other cases were hospitalized elsewhere. This three-year survey found a high rate of non-nosocomial IA cases and a high frequency of IA cases hospitalized in units other than haematology. Thus, this study shows the importance of IA surveillance in haematology units and all high-risk units.

[Subcutaneous abcesses due to Mycobacterium avium due to a reconstitution syndrome in AIDS patients]. / Abcès sous-cutanés à Mycobacterium avium liés à la reconstitution immunitaire chez les patients sida.

Clinical presentations of opportunistic infections in AIDS patients have dramatically changed since the introduction of HAART. The immune reconstitution syndrome (IRS) is typical of this change. The authors discuss the case of an AIDS female patient presenting with subcutaneous abcesses and abdominal lymph node enlargement due to Mycobacterium avium and occurring 10 weeks after initiation of HAART. This was related to the exacerbation of immune response against the bacteria that had previously infected the patient. Many cases of IRS involving M. avium have now been described, but cutaneous localisations remain infrequent. The treatment consists in HAART continuation associated with anti mycobacterial antibiotics and possibly anti inflammatory drugs.

The pathology of the neuronal cytoskeleton in Alzheimer's disease.

The two characteristic neuropathological lesions of Alzheimer's disease are the neurofibrillary tangles and the senile plaques. Neurofibrillary tangles are made of abnormal filaments (PHF) accumulating in neurons and mainly composed of a modified form of the microtubule-associated protein tau (PHF-tau). Senile plaques are composed of a cluster of dystrophic neurites surrounding an extracellular deposit of amyloid fibers made of a 42 amino-acid peptide (beta-amyloid peptide). The abnormal filaments contain the complete sequences of the different tau isoforms. The PHF-tau proteins can be distinguished from the normal tau proteins by the presence of several phosphorylated sites. One of these sites is phosphorylated by a calcium-calmodulin-dependent kinase. The relationship between PHF-tau and the cytoskeletal pathology in Alzheimer's disease is further discussed.

Performance of the Now Malaria rapid diagnostic test with returned travellers: a 2-year retrospective study in a French teaching hospital.

Malaria caused by Plasmodium falciparum remains the major life-threatening parasitic infection in the world. The number of cases in non-endemic countries continues to increase, and it is important that misdiagnosis of malaria should not occur, especially in non-immune travellers, because of the high risk of a fatal outcome. In a retrospective study of 399 sera, the Now Malaria rapid test was compared with the quantitative buffy coat (QBC) test and microbiological examination of thin blood films. Compared with the QBC test and thin blood films, the Now Malaria test had sensitivity and specificity values of 96.4% and 97%, respectively, for the detection of pure P. falciparum infection. A negative predictive value of 99.4% allows this test to be included in diagnostic strategies for patients presenting with clinical suspicion of malaria. Two false-negative results were associated with low levels of parasitaemia in the specimens. Thus, use of the Now Malaria test alone to detect P. falciparum infection in non-endemic countries could lead to misdiagnosis of malaria. This rapid diagnostic test should therefore be performed in association with another prompt traditional method such as examination of thin blood films.

[Immune reconstitution syndrome and mycobacterial disease during highly active antiretroviral therapy. Retrospective study of six cases]. / Reconstitution immunitaire et infections à mycobactéries sous traitement antirétroviral. Etude rétrospective de 6 observations.

INTRODUCTION: Soon after starting highly active antiretroviral therapy (HAART), some patients experience clinical deterioration due to the reactivation of their immune system. Mycobacteria are the principal agents complicating this immune reconstitution period. CASES: A retrospective examination of patients with mycobacterial disease before or shortly after beginning HAART at Grenoble University Hospital from January 2001 through July 2004 identified six subjects (among 650 outpatients per year) with a new or aggravated mycobacterial disease after starting HAART. Clinical manifestations were: adenopathy (4/6), hyperthermia (3/6), thoracic pain (2/6), abscess (2/6), and neurological deterioration (1/6). DISCUSSION: Severely immunosuppressed patients who begin HAART may reactivate or aggravate a mycobacterial disease such as tuberculosis. In such cases, current recommendations call for continuing HAART, beginning or continuing the antimycobacterial therapy, and considering corticosteroids on a case-by-case basis. For patients with AIDS, opportunistic infections that might be reactivated should be actively sought before HAART.

Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer's disease.

A disturbance of the microtubule network in neurons containing neurofibrillary tangles (NFT), one of the characteristic neuropathological lesions in Alzheimer's disease, has been advocated as a central physiopathological mechanism leading to neuronal dysfunction in NFT-containing neurons. The accumulation of "paired helical filament-tau," the main proteineous component of NFT, in affected neurons has been proposed to induce a decrease of microtubule stability in these cells. To further explore the hypothesis of a decrease in microtubule stability in Alzheimer's disease, we have investigated in this study the relative content in stable microtubules in neurons with different amount of NFT. We used a double immunocytochemical labeling technique with antibodies to tau (as a marker of NFT) and to acetylated alpha-tubulin (as a marker of stable microtubules) and rated on a semi-quantitative scale the tau and acetylated alpha-tubulin-immunoreactivities in the same neurons. We observed a strong reduction in acetylated alpha-tubulin immunoreactivity in most NFT-bearing neurons; a statistical relationship between tau and acetylated alpha-tubulin immunoreactivity was demonstrated, assuming an inverse relationship between the presence of tau-immunoreactive NFT and tubulin-immunoreactivity in neurons. This reduction was already seen in the neuronal population with a relatively lower tau-immunoreactivity, suggesting that reduction in acetylated alpha-tubulin immunoreactivity, and reduction in microtubule stability, could be an early event in these cells.

Lithium reduces tau phosphorylation: effects in living cells and in neurons at therapeutic concentrations.

BACKGROUND: The mechanism of action of lithium remains to be determined satisfactorily. Recent studies suggested a possible role in inhibiting glycogen synthase kinase-3 (GSK-3), previously shown to phosphorylate the protein tau. Tau is expressed mainly in neurons, where it functions to stabilize microtubules in a phosphorylation-dependent manner. METHODS: Neurons and transfected non-neuronal cells were treated with lithium and the phosphorylation of tau at multiple epitopes examined by western blotting and by immunocytochemistry. Using green fluorescent protein as a tag we examined the effects of lithium on phosphorylated tau in living cells. RESULTS: Lithium reversibly reduced tau phosphorylation at therapeutic concentrations, and even at high concentrations did not alter neuronal morphology. Green fluorescent protein tagged-tau when phosphorylated by GSK-3 was diffusely distributed; treatment with lithium resulted in association with microtubules and then bundle formation. Removing lithium allowed observation of the dissolution of bundles and gradual dissociation of tau from microtubules in living cells. CONCLUSIONS: Lithium may have multiple effects in brain, but at least one action is demonstrated to be a relative inhibition of GSK-3-induced tau phosphorylation. These results carry implications for future studies of the actions of mood-stabilizing drugs and indeed of the molecular mechanisms of affective disorders.

Neurodegenerative changes including altered tau phosphorylation and neurofilament immunoreactivity in mice transgenic for the serine/threonine kinase Mos.

Transgenic mice expressing the oncogenic protein-serine/threonine kinase Mos at high levels in the brain display progressive neuronal degeneration and gliosis. Gliosis developed in parallel with the onset of postnatal transgene expression and led to a dramatic increase in the number of astrocytes positive for GFAP, vimentin, and possibly tau. Interestingly, vimentin is normally expressed only in immature or neoplastic astrocytes, but appears to be induced to high levels in Mos-transgenic, mature astrocytes. Mos can activate mitogen activated protein kinase (MAPK) and MAPK has been implicated in Alzheimer-type tau phosphorylation. In the Mos-transgenic brain we found increased levels of phosphorylation at one epitope on tau containing serines 199 and 202 (numbering according to human tau), a pattern similar but not identical to that found in Alzheimer's disease. In addition, Mos-transgenic mice express a novel neurofilament-related protein that might be a proteolytic neurofilament heavy chain degradation product. These results suggest that activation of protein phosphorylation in neurons can result in changes in cytoskeletal proteins that might contribute to neuronal degeneration.

Modulation of PHF-like tau phosphorylation in cultured neurones and transfected cells.

Two cellular systems have been used to investigate the modulation of tau hyperphosphorylation. In the first system, the effects of the excitatory amino acid glutamate, the microtubule destabilising agent colchicine, and beta 25-35-amyloid peptide on tau phosphorylation were studied in rat cortical neurones in primary culture. Using immunocytochemistry and western blot analysis, we demonstrated that tau in these cultures is normally highly phosphorylated, but a proportion becomes rapidly dephosphorylated following treatment of the cultures with glutamate or colchicine. These changes in tau phosphorylation occurred prior to cell death. In the second system, the ability of p42 MAP and p44 MAP kinases, glycogen synthase kinases 3 alpha and 3 beta (GSK-3 alpha and GSK-3 beta) to phosphorylate tau in transfected COS cells was investigated. Both GSK-3 alpha and GSK-3 beta phosphorylated tau to produce a PHF-like state of phosphorylation but the MAP kinases failed to induce such a transformation in tau. These results suggest that aberrant regulation of GSK-3 alpha/beta may be a pathogenic mechanism in Alzheimer's disease.

Expression of tau mRNA and soluble tau isoforms in affected and non-affected brain areas in Alzheimer's disease.

In Alzheimer's disease (AD), selective expression of tau isoforms might underlie the susceptibility of different brain areas to develop neurofibrillary tangles and this pattern might change in the disease. In this study, we have analyzed in control subjects and in sporadic AD patients the pattern of expression of tau mRNA and tau proteins in areas unaffected (cerebellar cortex, white matter), moderately affected (occipital striate cortex, thalamus, caudate nucleus, and putamen) or strongly affected by neurofibrillary tangles (temporal and frontal associative cortex). After RT-PCR amplification, five products corresponding to the tau mRNAs containing exons 2 and 3, exon 2, without exons 2 or 3, with exon 10 and without exon 10 were identified. In control subjects, these five PCR products were present in all areas except in white matter, where transcripts with exons 2 or exons 2 and 3 were not identified. In AD patients, the same pattern of transcripts was observed in different areas, regardless of the presence of neurofibrillary lesions. After dephosphorylation of soluble tau proteins, the six tau isoforms were identified in the same areas by immunoblotting, including in the white matter, suggesting that most tau isoforms with exons 2 and 3 are transported along axons. The relative expression of 0N3R isoforms was higher in the temporal cortex than in the cerebellar cortex, both in control and AD subjects. The qualitative pattern of expression was identical in subjects with or without an APOE4 allele. Our results suggest that splicing regulation of the tau gene and the relative expression of tau isoforms are not significantly changed in sporadic cases of the disease, although differential expression of tau isoforms in temporal cortex might underlie this brain area susceptibility to neurofibrillary tangles formation.

Isolation of cDNAs coding for epitopes shared by microtubule-associated proteins and neurofibrillary tangle in Alzheimer's disease.

5 cross-hybridizing cDNA clones of sizes 2.2 (3 cDNAs), 1.3 and 0.8 kb corresponding to tau microtubule-associated protein have been isolated from a rat brain lambda gt11 expression library. Antibodies affinity-purified using the fusion protein encoded by the cDNAs were observed to label tau polypeptides on Western blots and Alzheimer's neurofibrillary tangles.