NeuroBioBank Publications

All published scientific findings derived from tissues and/or data obtained through the NeuroBioBank must acknowledge the NIH NeuroBioBank as the source.


A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer's disease
Feb. 2017

Abstract:

Currently, 5.4 million Americans suffer from AD, and these numbers are expected to increase up to 16 million by 2050. Despite tremendous research efforts, we still do not have drugs or agents that can delay, or prevent AD and its progression, and we still do not have early detectable biomarkers for AD. Multiple cellular changes have been implicated in AD, including synaptic damage, mitochondrial damage, production and accumulation of Aβ and phosphorylated tau, inflammatory response, deficits in neurotransmitters, deregulation of the cell cycle, and hormonal imbalance. Research into AD has revealed that miRNAs are involved in each of these cellular changes and interfere with gene regulation and translation. Recent discoveries in molecular biology have also revealed that microRNAs play a major role in post-translational regulation of gene expression. The purpose of this article is to review research that has assessed neuroprotective and neurodegenerative characteristics of microRNAs in brain samples from AD transgenic mouse models and patients with AD.

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How Studies of the Serotonin System in Macaque Models of Menopause Relate to Alzheimer's Disease1
Jan. 2017

Abstract:

Serotonin plays a key role in mood or affect, and dysfunction of the serotonin system has been linked to depression in humans and animal models. Depression appears prior to or coincident with overt symptoms of Alzheimer's disease (AD) in about 50% of patients, and some experts consider it a risk factor for the development of AD. In addition, AD is more prevalent in women, who also show increased incidence of depression. Indeed, it has been proposed that mechanisms underlying depression overlap the mechanisms thought to hasten AD. Women undergo ovarian failure and cessation of ovarian steroid production in middle age and the postmenopausal period correlates with an increase in the onset of depression and AD. This laboratory has examined the many actions of ovarian steroids in the serotonin system of non-human primates using a rhesus macaque model of surgical menopause with short or long-term estradiol (E) or estradiol plus progesterone (E+P) replacement therapy. In this mini-review, we present a brief synopsis of the relevant literature concerning AD, depression, and serotonin. We also present some of our data on serotonin neuron viability, the involvement of the caspase-independent pathway, and apoptosis-inducing factor in serotonin-neuron viability, as well as gene expression related to neurodegeneration and neuron viability in serotonin neurons from adult and aged surgical menopausal macaques. We show that ovarian steroids, particularly E, are crucial for serotonin neuron function and health. In the absence of E, serotonin neurons are endangered and deteriorating toward apoptosis. The possibility that this scenario may proceed or accompany AD in postmenopausal women seems likely.

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TDP-43 regulates endogenous retrovirus-K viral protein accumulation
Oct. 2016

Abstract:

The concomitant expression of neuronal TAR DNA binding protein 43 (TDP-43) and human endogenous retrovirus-K (ERVK) is a hallmark of ALS. Since the involvement of TDP-43 in retrovirus replication remains controversial, we sought to evaluate whether TDP-43 exerts an effect on ERVK expression. In this study, TDP-43 bound the ERVK promoter in the context of inflammation or proteasome inhibition, with no effect on ERVK transcription. However, over-expression of ALS-associated aggregating forms of TDP-43, but not wild-type TDP-43, significantly enhanced ERVK viral protein accumulation. Human astrocytes and neurons further demonstrated cell-type specific differences in their ability to express and clear ERVK proteins during inflammation and proteasome inhibition. Astrocytes, but not neurons, were able to clear excess ERVK proteins through stress granule formation and autophagy. In vitro findings were validated in autopsy motor cortex tissue from patients with ALS and neuro-normal controls. We further confirmed marked enhancement of ERVK in cortical neurons of patients with ALS. Despite evidence of enhanced stress granule and autophagic response in ALS cortical neurons, these cells failed to clear excess ERVK protein accumulation. This highlights how multiple cellular pathways, in conjunction with disease-associated mutations, can converge to modulate the expression and clearance of viral gene products from genomic elements such as ERVK. In ALS, ERVK protein aggregation is a novel aspect of TDP-43 misregulation contributing towards the pathology of this neurodegenerative disease.

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NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5' Long Terminal Repeat
Sept. 2016

Abstract:

Thousands of endogenous retroviruses (ERV), viral fossils of ancient germ line infections, reside within the human genome. Evidence of ERV activity has been observed widely in both health and disease. While this is most often cited as a bystander effect of cell culture or disease states, it is unclear which signals control ERV transcription. Bioinformatic analysis suggests that the viral promoter of endogenous retrovirus K (ERVK) is responsive to inflammatory transcription factors. Here we show that one reason for ERVK upregulation in amyotrophic lateral sclerosis (ALS) is the presence of functional interferon-stimulated response elements (ISREs) in the viral promoter. Transcription factor overexpression assays revealed independent and synergistic upregulation of ERVK by interferon regulatory factor 1 (IRF1) and NF-κB isoforms. Tumor necrosis factor alpha (TNF-α) and LIGHT cytokine treatments of human astrocytes and neurons enhanced ERVK transcription and protein levels through IRF1 and NF-κB binding to the ISREs. We further show that in ALS brain tissue, neuronal ERVK reactivation is associated with the nuclear translocation of IRF1 and NF-κB isoforms p50 and p65. ERVK overexpression can cause motor neuron pathology in murine models. Our results implicate neuroinflammation as a key trigger of ERVK provirus reactivation in ALS. These molecular mechanisms may also extend to the pathobiology of other ERVK-associated inflammatory diseases, such as cancers, HIV infection, rheumatoid arthritis, and schizophrenia.

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Gene expression elucidates functional impact of polygenic risk for schizophrenia
Sept. 2016

Abstract:

Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ~20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

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Alterations of miRNAs reveal a dysregulated molecular regulatory network in Parkinson's disease striatum.
Aug. 2016

Abstract:

Molecular adaptations in the striatum mediated by dopamine (DA) denervation and/or levodopa (L-dopa) treatments have been implicated in the motor deficits found in Parkinson's disease (PD). Alterations in inflammatory response mechanisms and glutamatergic neurotransmission are reported to play important roles in mediating these changes. However, the mechanisms mediating the molecular adaptations in the striatum are not well understood. Small non-coding microRNAs (miRNAs) influence numerous biological processes including the development and maintenance of striatal neurons by regulating gene expression post-transcriptionally. To investigate miRNA function in human PD striatum, we examined the global expression of miRNAs in postmortem putamen (putamen along with caudate forms the striatum) tissues obtained from PD patients and neurologically normal controls using Nanostring miRNA assays. We found that 6 miRNAs were significantly (p≤0.05) upregulated and 7 miRNAs were downregulated in PD putamen when compared with control. The differential expression (DE) of the 4 highest scoring miRNAs was further confirmed by reverse transcription polymerase chain reaction. Ingenuity pathway analysis demonstrated that these miRNAs are enriched in the processes of inflammatory responses. We found that the expression of DE miRNAs in PD putamen negatively correlates with the expression of gene transcripts implicated in inflammatory response with p53 and NF-kB as central signaling molecules. Taken together, our results suggest that in PD striatum, the DE miRNAs are associated with the oxidative stress pathway. This mechanism may contribute to the molecular adaptations and related motor complications found in PD.

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Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts
Aug. 2016

Abstract:

Genome-wide association studies have identified BIN1 within the second most significant susceptibility locus in late-onset Alzheimer's disease (AD). BIN1 undergoes complex alternative splicing to generate multiple isoforms with diverse functions in multiple cellular processes including endocytosis and membrane remodeling. An increase in BIN1 expression in AD and an interaction between BIN1 and Tau have been reported. However, disparate descriptions of BIN1 expression and localization in the brain previously reported in the literature and the lack of clarity on brain BIN1 isoforms present formidable challenges to our understanding of how genetic variants in BIN1 increase the risk for AD.

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Characterisation of interface astroglial scarring in the human brain after blast exposure: a post-mortem case series
Aug. 2016

Abstract:

No evidence-based guidelines are available for the definitive diagnosis or directed treatment of most blast-associated traumatic brain injuries, partly because the underlying pathology is unknown. Moreover, few neuropathological studies have addressed whether blast exposure produces unique lesions in the human brain, and if those lesions are comparable with impact-induced traumatic brain injury. We aimed to test the hypothesis that blast exposure produces unique patterns of damage, differing from that associated with impact-induced, non-blast traumatic brain injuries.

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VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease
Aug. 2016

Abstract:

Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD.

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mGlu5 positive allosteric modulation normalizes synaptic plasticity defects and motor phenotypes in a mouse model of Rett syndrome
May 2016

Abstract:

Rett syndrome (RS) is a neurodevelopmental disorder that shares many symptomatic and pathological commonalities with idiopathic autism. Alterations in protein synthesis-dependent synaptic plasticity (PSDSP) are a hallmark of a number of syndromic forms of autism; in the present work, we explore the consequences of disruption and rescue of PSDSP in a mouse model of RS. We report that expression of a key regulator of synaptic protein synthesis, the metabotropic glutamate receptor 5 (mGlu5) protein, is significantly reduced in both the brains of RS model mice and in the motor cortex of human RS autopsy samples. Furthermore, we demonstrate that reduced mGlu5 expression correlates with attenuated DHPG-induced long-term depression in the hippocampus of RS model mice, and that administration of a novel mGlu5 positive allosteric modulator (PAM), termed VU0462807, can rescue synaptic plasticity defects. Additionally, treatment of Mecp2-deficient mice with VU0462807 improves motor performance (open-field behavior and gait dynamics), corrects repetitive clasping behavior, as well as normalizes cued fear-conditioning defects. Importantly, due to the rationale drug discovery approach used in its development, our novel mGlu5 PAM improves RS phenotypes and synaptic plasticity defects without evoking the overt adverse effects commonly associated with potentiation of mGlu5 signaling (i.e. seizures), or affecting cardiorespiratory defects in RS model mice. These findings provide strong support for the continued development of mGlu5 PAMs as potential therapeutic agents for use in RS, and, more broadly, for utility in idiopathic autism.

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Pallidal neuronal apolipoprotein E in pantothenate kinase-associated neurodegeneration recapitulates ischemic injury to the globus pallidus.
Dec. 2015

Abstract:

Pantothenate kinase-associated neurodegeneration (PKAN) is a progressive movement disorder that is due to mutations in PANK2. Pathologically, it is a member of a class of diseases known as neurodegeneration with brain iron accumulation (NBIA) and features increased tissue iron and ubiquitinated proteinaceous aggregates in the globus pallidus. We have previously determined that these aggregates represent condensed residue derived from degenerated pallidal neurons. However, the protein content, other than ubiquitin, of these aggregates remains unknown. In the present study, we performed biochemical and immunohistochemical studies to characterize these aggregates and found them to be enriched in apolipoprotein E that is poorly soluble in detergent solutions. However, we did not determine a significant association between APOE genotype and the clinical phenotype of disease in our database of 81 cases. Rather, we frequently identified similar ubiquitin- and apolipoprotein E-enriched lesions in these neurons in non-PKAN patients in the penumbrae of remote infarcts that involve the globus pallidus, and occasionally in other brain sites that contain large γ-aminobutyric acid (GABA)ergic neurons. Our findings, taken together, suggest that tissue or cellular hypoxic/ischemic injury within the globus pallidus may underlie the pathogenesis of PKAN.

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F-box protein 7 mutations promote protein aggregation in mitochondria and inhibit mitophagy
Nov. 2015

Abstract:

The mutations of F-box protein 7 (FBXO7) gene (T22M, R378G and R498X) are associated with a severe form of autosomal recessive juvenile-onset Parkinson's disease (PD) (PARK 15). Here we demonstrated that wild-type (WT) FBXO7 is a stress response protein and it can play both cytoprotective and neurotoxic roles. The WT FBXO7 protein is vital to cell mitophagy and can facilitate mitophagy to protect cells, whereas mutant FBXO7 inhibits mitophagy. Upon stress, the endogenous WT FBXO7 gets up-regulated, concentrates into mitochondria and forms FBXO7 aggregates in mitochondria. However, FBXO7 mutations aggravate deleterious FBXO7 aggregation in mitochondria. The FBXO7 aggregation and toxicity can be alleviated by Proline, glutathione (GSH) and coenzyme Q10, whereas deleterious FBXO7 aggregation in mitochondria can be aggravated by prohibitin 1 (PHB1), a mitochondrial protease inhibitor. The overexpression of WT FBXO7 could lead to FBXO7 protein aggregation and dopamine neuron degeneration in transgenic Drosophila heads. The elevated FBXO7 expression and aggregation were identified in human fibroblast cells from PD patients. FBXO7 can also form aggregates in brains of PD and Alzheimer's disease. Our study provides novel pathophysiologic insights and suggests that FBXO7 may be a potential therapeutic target in FBXO7-linked neuron degeneration in PD.

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Sex differences in glutamate receptor gene expression in major depression and suicide
Sept. 2015

Abstract:

Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-d-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59=2.32, P=0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups. These data reveal further evidence that, in addition to the NMDA receptor, the AMPA, kainate and the metabotropic GluRs may be targets for the development of rapidly acting antidepressant drugs.

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