Detection of GSH with a dual-mode biosensor based on carbon quantum dots prepared from dragon fruit peel and the T-Hg(II)-T mismatch.

Glutathione (GSH) is commonly used as a diagnostic biomarker for many diseases. In this study, based on carbon quantum dots prepared from dragon fruit peel (D-CQDs) and the T-Hg(II)-T mismatch, a dual-mode biosensor was developed for the detection of GSH. This system consists of two single-stranded DNA (ssDNA). DNA1 was the T-rich sequence; DNA2 was attached to streptavidin-coated magnetic beads and consisted of T-rich and G-rich fragments. Due to the presence of Hg(II), the T-Hg(II)-T mismatch was formed between T-rich fragments of two ssDNA. In the presence of GSH, Hg(II) detached from dsDNA and bound with GSH to form a new complex. The G-rich fragment assembled with the hemin shed from D-CQDs to form the G-quadruplex/hemin complex. At this time, in fluorescence mode, the fluorescence of D-CQDs quenched by hemin could be restored. In colorimetric mode, after the magnetic beads separate, a visual signal could be produced by catalyzing the oxidation of ABTS using the peroxide-like activity of the G-quadruplex/hemin complex. This biosensor in both fluorescence mode and colorimetric mode had excellent selectivity and sensitivity, and the limit of detection was 0.089 µM and 0.26 µM for GSH, respectively. Moreover, the proposed dual-mode biosensor had good application prospects for detection of GSH.

Hydroxychloroquine-induced pigmentation in rheumatic diseases: prevalence, clinical features and influencing factors.

OBJECTIVE: To describe the clinical features of Chinese patients with hydroxychloroquine (HCQ)-induced pigmentation and analyze the potential risk factors associated with HCQ-induced pigmentation. METHODS: A cross-sectional study was conducted over a duration of 7 months, during which patients who had received HCQ treatment for >6 months were included. Data was collected through a structured questionnaire that encompassed demographic and geographic characteristics, information on HCQ and concomitant medication usage, sun exposure characteristics, and hyperpigmentation-related characteristics. Univariate and multivariate analyses were employed to calculate the statistical association between HCQ-induced pigmentation and multiple variables. RESULTS: Out of 316 patients, 83 (26.3%) patients presented hyperpigmentation during HCQ treatment. Hyperpigmentation presented after a median duration of HCQ treatment of 12 months (interquartile range, 6.0 months-30.0 months) with a median cumulative dose of 108 g of HCQ (interquartile range, 36-288 g). The most frequently affected sites of pigmentation were the face (60.2%), lower limbs (36.1%), and hands (20.5%). There was a linear decrease in the incidence of pigmentation with increasing daily sun exposure time (p= 0.030). In the multivariate analysis, variables (cumulative HCQ dose and daily sun exposure time) were included in the final models. The results revealed an independent correlation between HCQ-induced pigmentation and daily sun exposure exceeding 1 h (OR: 0.431; 95%CI: 0.208-0.892; p= 0.023). CONCLUSIONS: The occurrence of HCQ-induced pigmentation is not uncommon, with an incidence rate of 26.3%. Daily sun exposure time exhibited a protective effect against HCQ-induced pigmentation.

A Fluorescence Biosensor Based on Carbon Quantum Dots Prepared from Pomegranate Peel and T-Hg2+-T Mismatch for Hg2+ Detection.

Mercury ions (Hg2+) can cause damage to human health, and thus, the study of the detection of Hg2+ is extraordinarily important in daily life. This work reported a fluorescence biosensor for the detection of Hg2+. The key point of this strategy was that the fluorescence of carbon quantum dots made from pomegranate peel (P-CQDs) was quenched by hemin, and restored after G-quadruplex binding with hemin. The presence of Hg2+ caused thymine (T)-rich DNA fragments to form T-Hg2+-T mismatches, and this change allowed the release of G-quadruplex. G-quadruplex could change the fluorescence of hemin/P-CQDs. P-CQDs exhibited excellent properties through characterization analysis, such as transmission electron microscope, X-ray photoelectron spectroscopy and Fourier transform infrared. This proposed fluorescence detection strategy established the linear ranges of Hg2+ from 1 nM to 50 nM. In conclusion, this simple biosensor had the advantages of strong sensitivity, high selectivity, and low cost for Hg2+ detection in environmental water samples.

Recent advances of the biological and biomedical applications of CRISPR/Cas systems.

The clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated endonuclease (Cas) system, referred to as CRISPR/Cas system, has attracted significant interest in scientific community due to its great potential in translating into versatile therapeutic tools in biomedical field. For instance, a myriad of studies has demonstrated that the CRISPR/Cas system is capable of detecting various types of viruses, killing antibiotic-resistant bacteria, treating inherited genetic diseases, and providing new strategies for cancer therapy. Furthermore, CRISPR/Cas systems are also exploited as research tools such as genome engineering tool that allows researchers to interrogate the biological roles of unexplored genes or uncover novel functions of known genes. Additionally, the CRISPR/Cas system has been employed to edit the genome of a wide range of eukaryotic, prokaryotic organisms and experimental models, including but not limited to mammalian cells, mice, zebrafish, plants, yeast, and Escherichia coli. The present review mainly focuses on summarizing recent discoveries regarding the type II CRISPR/Cas9 and type VI CRISPR/Cas13a systems to give researchers a glimpse of their potential applications in the biological and biomedical field.

Corrigendum: A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood.

[This corrects the article DOI: 10.3389/fneur.2021.675616.].

A Novel Variation in the Mitochondrial Complex I Assembly Factor NDUFAF5 Causes Isolated Bilateral Striatal Necrosis in Childhood.

Background: Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN results in high morbidity and mortality among infants and children, and its diagnosis is clinically challenging due to several overlapping disease phenotypes. Therefore, a precise genetic diagnosis is urgently needed for accurate genetic counseling and improved prognostic outcomes as well. Objective: To identify novel missense mutations in the NDUFAF5 gene as a cause of childhood BSN in members of a Chinese family and summarize the clinical characteristics of patients with the NDUFAF5 gene mutations. Methods: This study included a large family living in a remote northwestern area of China. Three siblings developed a neurological disorder characterized by generalized dystonia within the first decade of their lives. Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral lesions of the putamen. Biochemical and genetic approaches were used to identify the cause of BSN. Results: Sequence analysis showed no pathogenic variation in PANK2, SLC25A19, SLC19A3, and NUP62 genes and in the entire mitochondrial genome as well. Whole-exome sequencing revealed compound heterozygous mutations consisting of NDUFAF5:c.425A > C(p.E142A) and c.836T > G (p.M279R). The father, a healthy sister, and a healthy brother of the affected siblings carried the c.836T > G mutation, and the mother carried the c.425A > C mutation. These variants were absent in 100 ethnically matched non-BSN controls. In silico analysis demonstrated that the E142A and M279R mutations in NDUFAF5 protein significantly perturbed the normal conformation of the protein due to alterations in the hydrogen bonding patterns around the evolutionarily conserved catalytic domains, leading to its loss of function in the early stage of mitochondrial complex I assembly. Conclusions: We identified a novel compound heterozygous mutation (c.425A > C and c.836T > G) in the NDUFAF5 gene as the potential cause of autosomal recessive childhood BSN, which extended the pathogenic variation spectrum of the NDUFAF5 gene. This study provides substantial evidence for further improvement of genetic counseling and better clinical management of BSN affected individuals.

Encephalitis with reversible splenial and deep cerebral white matter lesions associated with Epstein-Barr virus infection in adults.

BACKGROUND: Approximately 200 cases of mild encephalitis with reversible splenial (MERS) and deep cerebral white matter lesions have been reported since MERS was first defined in 2004. MERS occurs more frequently in children; in adults, only ~60 cases have been reported. Until now, only four cases of MERS in adults have been associated with Epstein-Barr virus (EBV). CASE PRESENTATION: We report three adult cases of MERS associated with EBV infection in China. For all three patients, cranial magnetic resonance imaging (MRI) indicated solitary reversible splenial and/or perilateral ventricle white matter lesions with reduced diffusion. In the present report, all patients were adults presenting with high fever, headache, apathy, and confusion, as well as significant signs of meningeal inflammation. These symptoms peaked 10-14 days after disease onset, with serious hyponatremia (112-129 mmol/L), an elevated cerebrospinal fluid white blood cell count (80-380/mm3), and significantly increased protein levels (1,010-1,650 mg/dL). Cranial MRI indicated abnormal signal intensity in the splenium of corpus callosum and symmetrically reversible lesions scattered in the thalamus and deep cerebral white matter. The clinical symptoms tended to improve after ~10-14 days of antiviral treatment. However, these patients recovered more slowly than patients with viral meningitis. CONCLUSION: MERS associated with EBV infection in adults occurs less frequently but with more severe symptoms than in children. EBV infection should be considered for patients with MERS symptoms. MERS has a good prognosis.

Detection of hyperphosphorylated tau protein and α-synuclein in spinal cord of patients with Alzheimer's disease.

The aim of this study was to investigate the neuropathological features of the spinal cord in patients suffering with Alzheimer's disease (AD). Spinal cord tissue collected from three AD patients and eight controls was selected for the study. Data were collected at T2, T8, T10, L4, and S2 spinal levels. The sections were subjected to hematoxylin and eosin and Gallyas-Braak staining methods and then were immunostained with antibodies such as phosphorylated tau protein (AT8), α-synuclein, Aß, amyloid precursor protein, ubiquitin, and TDP-43. Pathological changes exhibited by the biomarkers were detected by microscopy. Neurofibrillary tangles (NFTs) were detectable in spinal anterior horn motor neurons in two of the three AD patients. AT8-positive axons or axon-like structures and AT8 expression in glial cells were detected in all three AD cases. Hyperphosphorylation of tau protein was detected in spinal anterior horn cells, glial cells, and axons, and its severity was associated with NFTs in the brain tissue. α-Synuclein-positive Lewy bodies and scattered Lewy-like neuritis were detected in the medial horn of the thoracic spinal cord and ventral sacral gray matter, respectively, in one patient who had AD with Lewy bodies. Neither amyloid deposition nor amyloid precursor protein and TDP-43 expression was detected in the spinal cord of AD patients. Spinal cord of AD patients was observed to contain phosphorylated tau protein and α-synuclein immunoreactive structures, which may play a role in dyskinesia and autonomic dysfunction in advanced AD.

[Efficacy and safety of ropinirole in the treatment of Parkinson's disease: a multi-center, randomized, double-blind and bromocriptine-controlled trial].

OBJECTIVE: To explore the efficacy and safety of ropinirole in the treatment of Parkinson's disease. METHODS: From November 2005 to April 2007, a total of 221 subjects from 7 hospitals of Beijing, Lanzhou and Wuhan participated in a 12-week multi-center, randomized, bromocriptine-controlled, double-blind, double-dummy and parallel-group trial. The efficacy of ropinirole was assessed with the unified Parkinson's disease rating scale (UPDRS) score, "off" time according to the patient's diary and the overall evolution of clinical efficacy. The safety was assessed on the basis of adverse events, blood pressure, pulse, laboratory measurement and electrocardiographic recordings. And the statistical analyses were performed with t, paired t, χ(2) and covariance tests. RESULTS: In the intent-to-treat population, the average UPDRSIII score decreased to (11 ± 9) in ropinirole group and (11 ± 10) in bromocriptine group while the UPDRSIIscore decreased to (4 ± 4) and (3 ± 5) respectively at Week 12 versus baseline. It showed that ropinirole was non-inferior to bromocriptine. The "off" time at Week 12 [(3.0 ± 1.2)h, (3.8 ± 1.6)h] versus baseline [(4.2 ± 2.0)h, (4.4 ± 1.7)h] decreased (t = 10.772, t = 5.746, P = 0.000) in ropinirole and bromocriptine groups. Ropinirole offered a better overall improvement rate (q = 7.241, P = 0.007). The adverse events occurring at a ratio of over 5% caused by ropinirole included orthostatic hypotension, nausea, dizziness, upper abdominal discomfort, insomnia and palpitation. No significant difference existed in the frequency of adverse events between two groups. CONCLUSIONS: Ropinirole is both effective and safe in the treatment of Chinese patients with Parkinson's disease.

Disruption of neocortical histone H3 homeostasis by soluble Aß: implications for Alzheimer's disease.

Amyloid-ß peptide (Aß) fragment misfolding may play a crucial role in the progression of Alzheimer's disease (AD) pathophysiology as well as epigenetic mechanisms at the DNA and histone level. We hypothesized that histone H3 homeostasis is disrupted in association with the appearance of soluble Aß at an early stage in AD progression. We identified, localized, and compared histone H3 modifications in multiple model systems (neural-like SH-SY5Y, primary neurons, Tg2576 mice, and AD neocortex), and narrowed our focus to investigate 3 key motifs associated with regulating transcriptional activation and inhibition: acetylated lysine 14, phosphorylated serine 10 and dimethylated lysine 9. Our results in vitro and in vivo indicate that multimeric soluble Aß may be a potent signaling molecule indirectly modulating the transcriptional activity of DNA by modulating histone H3 homeostasis. These findings reveal potential loci of transcriptional disruption relevant to AD. Identifying genes that undergo significant epigenetic alterations in response to Aß could aid in the understanding of the pathogenesis of AD, as well as suggesting possible new treatment strategies.

Anti-N-methyl-D-aspartate receptor encephalitis with serum anti-thyroid antibodies and IgM antibodies against Epstein-Barr virus viral capsid antigen: a case report and one year follow-up.

BACKGROUND: Anti-N-methyl-D-aspartate receptor encephalitis is an increasingly common autoimmune disorder mediated by antibodies to certain subunit of the N-methyl-D-aspartate receptor. Recent literatures have described anti-thyroid and infectious serology in this encephalitis but without follow-up. CASE PRESENTATION: A 17-year-old Chinese female patient presented with psychiatric symptoms, memory deficits, behavioral problems and seizures. She then progressed through unresponsiveness, dyskinesias, autonomic instability and central hypoventilation during treatment. Her conventional blood work on admission showed high titers of IgG antibodies to thyroglobulin, thyroid peroxidase and IgM antibodies to Epstein-Barr virus viral capsid antigen. An immature ovarian teratoma was found and removal of the tumor resulted in a full recovery. The final diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was made by the identification of anti-N-methyl-D-aspartate receptor antibodies in her cerebral spinal fluid. Pathology studies of the teratoma revealed N-methyl-D-aspartate receptor subunit 1 positive ectopic immature nervous tissue and Epstein-Barr virus latent infection. She was discharged with symptoms free, but titers of anti-thyroid peroxidase and anti-thyroglobulin antibodies remained elevated. One year after discharge, her serum remained positive for anti-thyroid peroxidase and anti-N-methyl-D-aspartate receptor antibodies, but negative for anti-thyroglobulin antibodies and IgM against Epstein-Barr virus viral capsid antigen. CONCLUSIONS: Persistent high titers of anti-thyroid peroxidase antibodies from admission to discharge and until one year later in this patient may suggest a propensity to autoimmunity in anti- N-methyl-D-aspartate receptor encephalitis and support the idea that neuronal and thyroid autoimmunities represent a pathogenic spectrum. Enduring anti-N-methyl-D-aspartate receptor antibodies from admission to one year follow-up but seroreversion of Epstein-Barr virus viral capsid antigen IgM may raise the important issue of elucidating the triggers and boosters of anti- N-methyl-D-aspartate receptor encephalitis.

A case of Hashimoto encephalopathy: clinical manifestation, imaging, pathology, treatment, and prognosis.

INTRODUCTION: Hashimoto encephalopathy is a rare encephalopathy with positive antithyroid antibodies and normal thyroid function. We describe the clinical manifestations, neuroimaging, and histopathologic changes in a 52-year-old female with Hashimoto encephalopathy. RESULTS: The neuroimaging changes are multifocal abnormalities in cortical and subcortical areas bilaterally not enhanced by gadolinium. After high doses of corticosteroid therapy, the changes rapidly disappeared with marked improvement of clinical symptoms. CONCLUSIONS: This case shows the importance of assessment of antithyroid antibodies in patients with rapidly progressive cognitive dysfunction with/without the history of abnormality of thyroid function.

High throughput monitoring of amyloid-ß(42) assembly into soluble oligomers achieved by sensitive conformation state-dependent immunoassays.

Accumulation of small soluble assemblies of amyloid-ß (Aß)(42) in the brain is thought to play a key role in the pathogenesis of Alzheimer's disease. As a result, there has been much interest in finding small molecules that inhibit the formation of synaptotoxic Aß(42) oligomers that necessitates sensitive methods for detecting the initial steps in the oligomerization of Aß(42). Modeling suggests that oligomerized Aß(42) adopts a conformation in which the C-terminus is embedded in the center, whereas the N-terminus is exposed at the periphery of the oligomer. Here we report that an inverse change in Aß(42) C-terminal and N-terminal epitope accessibility provides the basis of a sensitive method for assessing early steps in Aß(42) oligomerization. Using ELISA and AlphaLISA, we found that Aß(42) C-terminal immunoreactivity decreased in a time- and concentration-dependent manner under conditions favoring oligomerization. This reduction was accompanied by an increase in the N-terminal immunoreactivity, suggesting that assemblies with multiple exposed N-terminal epitopes were detected. Importantly the assay generates a robust window between monomers and oligomers at as low as 1 nM Aß(42). Using this assay, known oligomerization inhibitors produced a dose-dependent unmasking of the Aß(42) C-terminal epitope. After automation, the assay proved to be highly reproducible and effective for high throughput screening of small molecules that inhibit Aß(42) oligomerization.

Inhibition of calcineurin-mediated endocytosis and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid beta oligomer-induced synaptic disruption.

Synaptic degeneration, including impairment of synaptic plasticity and loss of synapses, is an important feature of Alzheimer disease pathogenesis. Increasing evidence suggests that these degenerative synaptic changes are associated with an accumulation of soluble oligomeric assemblies of amyloid beta (Abeta) known as ADDLs. In primary hippocampal cultures ADDLs bind to a subpopulation of neurons. However the molecular basis of this cell type-selective interaction is not understood. Here, using siRNA screening technology, we identified alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits and calcineurin as candidate genes potentially involved in ADDL-neuron interactions. Immunocolocalization experiments confirmed that ADDL binding occurs in dendritic spines that express surface AMPA receptors, particularly the calcium-impermeable type II AMPA receptor subunit (GluR2). Pharmacological removal of the surface AMPA receptors or inhibition of AMPA receptors with antagonists reduces ADDL binding. Furthermore, using co-immunoprecipitation and photoreactive amino acid cross-linking, we found that ADDLs interact preferentially with GluR2-containing complexes. We demonstrate that calcineurin mediates an endocytotic process that is responsible for the rapid internalization of bound ADDLs along with surface AMPA receptor subunits, which then both colocalize with cpg2, a molecule localized specifically at the postsynaptic endocytic zone of excitatory synapses that plays an important role in activity-dependent glutamate receptor endocytosis. Both AMPA receptor and calcineurin inhibitors prevent oligomer-induced surface AMPAR and spine loss. These results support a model of disease pathogenesis in which Abeta oligomers interact selectively with neurotransmission pathways at excitatory synapses, resulting in synaptic loss via facilitated endocytosis. Validation of this model in human disease would identify therapeutic targets for Alzheimer disease.

[Studies on heredity rule of the first genealogy regarding fatal familial insomnia in Henan province].

OBJECTIVE: To investigate the epidemiological, genealogic characteristic, familial history of the families with fatal familial insomnia, its clinical and pathological features as well as the heredity rule of related genes. METHODS: 135 familial members of 7 eras were studied. Vein blood samples from patients as well as from some familial members were collected. PRNP gene was studied with PCR, its serial was determined and then authenticated with Nsp I . Brain tissue was obtained for neuropathological test and PrP(Sc) test with Western blot method. RESULTS: Clinical symptoms of the 2 diagnosed cases were typical. 11 familial members died of similar neural disease. 32 samples of their familial members, codon at D178N of PRNP of 11 members was mutated, with mutation rate as 34.38% while D129N showed as methionine. Brain tissue of both probands denaturalized into spongiform and the nerve fiber was absent but PrP(Sc) protein was identified. CONCLUSION: Genealogy was described in the family with fatal familial insomnia since the patients had typical clinical symptoms and pathological characteristics. It seemed necessary to confirm cases of fatal familial insomnia and their genealogy with epidemiological data and to investigate its gene characteristics as well as with neuropathological and Western blot tests.

Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}.

Accumulation of amyloid beta (Abeta) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of Abeta. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied Abeta oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to Abeta aggregation and subsequent synaptic loss.

Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers.

Synapse deterioration underlying severe memory loss in early Alzheimer's disease (AD) is thought to be caused by soluble amyloid beta (Abeta) oligomers. Mechanistically, soluble Abeta oligomers, also referred to as Abeta-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.

Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease.

Characterized as a peripheral metabolic disorder and a degenerative disease of the central nervous system respectively, it is now widely recognized that type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common abnormalities including impaired glucose metabolism, increased oxidative stress, insulin resistance and amyloidogenesis. Several recent studies suggest that this is not an epiphenomenon, but rather these two diseases disrupt common molecular pathways and each disease compounds the progression of the other. For instance, in AD the accumulation of the amyloid-beta peptide (Abeta), which characterizes the disease and is thought to participate in the neurodegenerative process, may also induce neuronal insulin resistance. Conversely, disrupting normal glucose metabolism in transgenic animal models of AD that over-express the human amyloid precursor protein (hAPP) promotes amyloid-peptide aggregation and accelerates the disease progression. Studying these processes at a cellular level suggests that insulin resistance and Abeta aggregation may not only be the consequence of excitotoxicity, aberrant Ca(2+) signals, and proinflammatory cytokines such as TNF-alpha, but may also promote these pathological effectors. At the molecular level, insulin resistance and Abeta disrupt common signal transduction cascades including the insulin receptor family/PI3 kinase/Akt/GSK3 pathway. Thus both disease processes contribute to overlapping pathology, thereby compounding disease symptoms and progression.

A patient with Creutzfeldt-Jakob disease with an insertion of 7 octa-repeats in the PRNP gene: molecular characteristics and clinical features.

BACKGROUND: We evaluated the features of neuropathology, abnormal prion protein (PrP) molecules, and clinical data of a Chinese woman diagnosed with familiar Creutzfeldt-Jakob disease (CJD), having 7 octa-repeats inserted with codon 129 methionine homozygote in the PRNP gene. METHODS: Neuropathologic characteristics of the brain were analyzed by hemotoxylin-eosin stain and electronic microscopy. The presence of abnormal PrP in brains was detected by proteinase K and PrP molecules were evaluated by deglycosylation assay. RESULTS: Spongiform degeneration, with diffuse neuronal loss and mild astrocytic gliosis, as well as with profound degeneration of neurons and astrocytes was observed. Proteinase K-resistant PrP was deposited widely in various regions of the brain. Calculation of the glycosylation ratios of proteinase K-resistant PrP molecules identified that the monoglycosyl isomer was predominant. PrP deglycosylation tests allowed for the identification of a predominant 19-kDa PrP signal that represents a partially proteolytic C-terminal segment, a 27-kDa band that represents the full-length wild-type PrP molecule, and a 30-kDa band that probably corresponds to the full-length mutant PrP molecule. CONCLUSION: : Sporadic CJD-like neuropathologic changes and deposits of proteinase K-resistant PrP have been identified in this familiar CJD case with a 168 base pair nucleotide insertion. The clinical features differ from previously reported cases that had 7 octa-repeat insertion, but bear similarities to sporadic CJD.