Browsing by Author "Ray, Balmiki"
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Item CORRECTION: Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease(Springer Nature, 2020-03-02) Ray, Balmiki; Maloney, Bryan; Sambamurti, Kumar; Karnati, Hanuma K.; Nelson, Peter T.; Greig, Nigel H.; Lahiri, Debomoy K.; Psychiatry, School of MedicineCorrection to: Translational Psychiatry 10.1038/s41398-020-0709-x published online 03 February 2020 The original article contained few errors: Hanuma K. Karnati’s name was misstated in the author list, references 2 and 55 referred to the wrong sources, and the authors wanted to expand on their discussion of ChEIs on page 13. These errors have all been updated in the XML, PDF, and HTML versions of this article.Item Effects of Reducing Norepinephrine Levels via DSP4 Treatment on Amyloid-β Pathology in Female Rhesus Macaques (Macaca Mulatta)(IOS Press, 2019) Duffy, Kara B.; Ray, Balmiki; Lahiri, Debomoy K.; Tilmont, Edward M.; Tinkler, Gregory P.; Herbert, Richard L.; Greig, Nigel H.; Ingram, Donald K.; Ottinger, Mary Ann; Mattison, Julie A.; Psychiatry, School of MedicineThe degeneration in the locus coeruleus associated with Alzheimer's disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer's disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine β-hydroxylase staining and increased amyloid-β load in the aged group, and the proportion of potentially toxic amyloid-β42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer's disease, but further refinement is necessary.Item Impact of acamprosate on plasma amyloid-β precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker(Elsevier, 2014-12) Erickson, Craig A.; Ray, Balmiki; Maloney, Bryan; Wink, Logan K.; Bowers, Katherine; Schaefer, Tori L.; McDougle, Christopher J.; Sokol, Deborah K.; Lahiri, Debomoy K.; Department of Psychiatry, IU School of MedicineBACKGROUND: Understanding of the pathophysiology of autism spectrum disorder (ASD) remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-β precursor protein (APP), secreted APPα (sAPPα), has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPα holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and deficient GABAergic neurotransmission in the disorder. With this in mind, acamprosate, a novel modulator of glutamate and GABA function, has been studied in ASD. No data is available on the impact of glutamate or GABA modulation on sAPPα function. METHODS: Plasma APP derivative levels pre- and post-treatment with acamprosate were determined in two pilot studies involving youth with idiopathic and fragile X syndrome (FXS)-associated ASD. We additionally compared baseline APP derivative levels between youth with FXS-associated or idiopathic ASD. RESULTS: Acamprosate use was associated with a significant reduction in plasma sAPP(total) and sAPPα levels but no change occurred in Aβ40 or Aβ42 levels in 15 youth with ASD (mean age: 11.1 years). Youth with FXS-associated ASD (n = 12) showed increased sAPPα processing compared to age-, gender- and IQ-match youth with idiopathic ASD (n = 11). CONCLUSIONS: Plasma APP derivative analysis holds promise as a potential biomarker for use in ASD targeted treatment. Reduction in sAPP (total) and sAPPα may be a novel pharmacodynamic property of acamprosate. Future study is required to address limitations of the current study to determine if baseline APP derivative analysis may predict subgroups of persons with idiopathic or FXS-associated ASD who may respond best to acamprosate or to potentially other modulators of glutamate and/or GABA neurotransmission.Item Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism(Elsevier, 2017-01) Erickson, Craig A.; Ray, Balmiki; Wink, Logan K.; Bayon, Baindu L.; Pedapat, Ernest V.; Shaffer, Rebecca; Schaefer, Tori L.; Lahiri, Debomoy K.; Psychiatry, School of MedicineBACKGROUND: Dysregulation of extracellular signal-related kinase (ERK) activity has been potentially implicated in the pathophysiology of autistic disorder (autism). ERK is part of a central intracellular signaling cascade responsible for a myriad of cellular functions. ERK is expressed in peripheral blood lymphocytes, and measurement of activated (phosphorylated) lymphocytic ERK is commonly executed in many areas of medicine. We sought to conduct the first study of ERK activation in humans with autism by utilizing a lymphocytic ERK activation assay. We hypothesized that ERK activation would be enhanced in peripheral blood lymphocytes from persons with autism compared to those of neurotypical control subjects. METHOD: We conducted an initial study of peripheral lymphocyte ERK activation in 45 subjects with autism and 26 age- and gender-matched control subjects (total n = 71). ERK activation was measured using a lymphocyte counting method (primary outcome expressed as lymphocytes staining positive for cytosolic phosphorylated ERK divided by total cells counted) and additional Western blot analysis of whole cell phosphorylated ERK adjusted for total ERK present in the lymphocyte lysate sample. RESULTS: Cytosolic/nuclear localization of pERK activated cells were increased by almost two-fold in the autism subject group compared to matched neurotypical control subjects (cell count ratio of 0.064 ± 0.044 versus 0.034 ± 0.031; p = 0.002). Elevated phosphorylated ERK levels in whole cell lysates also showed increased activated ERK in the autism group compared to controls (n = 54 total) in Western blot analysis. CONCLUSIONS: The results of this first in human ERK activation study are consistent with enhanced peripheral lymphocytic ERK activation in autism, as well as suggesting that cellular compartmentalization of activated ERK may be altered in this disorder. Future work will be required to explore the impact of concomitant medication use and other subject characteristics such as level of cognitive functioning on ERK activation.Item Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer's disease(Springer, 2014-07) Counts, Scott; Ray, Balmiki; Mufson, Elliott J.; Perez, Sylvia E.; He, Bin; Lahiri, Debomoy K.; Department of Psychiatry, IU School of MedicineIntravenous immunoglobulin (IVIG) has shown limited promise so far in human clinical studies on Alzheimer's disease (AD), yet overwhelmingly positive preclinical work in animals and human brain cultures support the notion that the therapy remains potentially efficacious. Here, we elaborate on IVIG neuropreservation by demonstrating that IVIG protects human primary neurons against oxidative stress in vitro and that IVIG preserves antioxidant defense mechanisms in vivo. Based on these results, we propose the following translational impact: If the dosage and treatment conditions are adequately optimized, then IVIG treatment could play a significant role in preventing and/or delaying the progression of neurodegenerative diseases, such as AD. We suggest that IVIG warrants further investigation to fully exploit its potential as an anti-oxidant, neuroprotective and synapto-protecting agent.Item MicroRNA-339-5p down-regulates protein expression of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer disease subjects(ASBMB, 2014-02-21) Long, Justin M.; Ray, Balmiki; Lahiri, Debomoy; Department of Medical & Molecular Genetics, IU School of MedicineAlzheimer disease (AD) results, in part, from the excess accumulation of the amyloid-β (Aβ) peptide as neuritic plaques in the brain. The short Aβ peptide is derived from the large transmembrane Aβ precursor protein (APP). The rate-limiting step in the production of Aβ from APP is mediated by the β-site APP-cleaving enzyme 1 (BACE1). Dysregulation of BACE1 levels leading to excess Aβ deposition is implicated in sporadic AD. Thus, elucidating the full complement of regulatory pathways that control BACE1 expression is key to identifying novel drug targets central to the Aβ-generating process. MicroRNAs (miRNAs) are expected to participate in this molecular network. Here, we identified a known miRNA, miR-339-5p, as a key contributor to this regulatory network. Two distinct miR-339-5p target sites were predicted in the BACE1 3'-UTR by in silico analyses. Co-transfection of miR-339-5p with a BACE1 3'-UTR reporter construct resulted in significant reduction in reporter expression. Mutation of both target sites eliminated this effect. Delivery of the miR-339-5p mimic also significantly inhibited expression of BACE1 protein in human glioblastoma cells and human primary brain cultures. Delivery of target protectors designed against the miR-339-5p BACE1 3'-UTR target sites in primary human brain cultures significantly elevated BACE1 expression. Finally, miR-339-5p levels were found to be significantly reduced in brain specimens isolated from AD patients as compared with age-matched controls. Therefore, miR-339-5p regulates BACE1 expression in human brain cells and is most likely dysregulated in at least a subset of AD patients making this miRNA a novel drug target.Item Regulation of Proteins Implicated in Alzheimer’s Disease by MicroRNAs(Office of the Vice Chancellor for Research, 2013-04-05) Chopra, Nipun; Long, Justin M.; Ray, Balmiki; Obukhov, Alexander G.; Lahiri, Debomoy K.Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the deposition of Amyloid-Beta (Aβ) peptide in the brain. This toxic peptide is generated by the sequential cleavage of Amyloid Precursor Protein (APP) by Beta-site APP-cleaving enzyme-1 (BACE-1) and γ-secretase. The disorder is also characterized by the perturbation of calcium homeostasis in neurons. MicroRNAs are short, single-stranded RNAs that are able to influence protein expression by targeting the 3’ Untranslated region (UTR) or 5’ UTR of mRNAs. Previous work in our laboratory has shown that miR-101, miR-153 and miR-346 can regulate APP whereas miR-339-5p can lower BACE1 expression. Here, we aim to reduce APP, BACE1 and Aβ levels, in vitro, by the addition of microRNAs that target the 3’ UTR of APP and BACE1. We show that in a human astrocytoma-glioblastoma (U373) cell line, the expression of BACE1 protein is significantly reduced compared to the mock condition upon transfecting miR-298, miR-328 and miR-144. miR-298 also reduces Aβ levels in these cells. Similarly, in HeLa cells, we show that miR-520c, miR-20b and miR-144 produce a reduction in APP expression compared to both mock and a negative control microRNA mimic. Additionally, we observed that knocking down APP using siRNA, but not knocking down BACE1, lowers basal intracellular calcium levels as well as changes the kinetics of Potassium Chloride (KCl)-induced intracellular calcium influx in a human fetal brain (HFB) culture, when compared to control. miR-346 increases basal calcium levels, but does not affect KCl-induced calcium transients in our HFB culture. Taken together, these results show that miRNAs can influence both the protein expression as well as calcium homeostasis in different human cell culture models. By reducing levels of proteins implicated in AD pathology and by reversing calcium dysregulation, our results will benefit AD research and generate possibilities for novel therapeutics.Item Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer's disease(Springer Nature, 2020-02) Ray, Balmiki; Maloney, Bryan; Sambamurti, Kumar; Karnati, Hanuma K.; Nelson, Peter T.; Greig, Nigel H.; Lahiri, Debomoy K.; Psychiatry, School of MedicineRivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer’s disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases– Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.Item Synthesis of the Alzheimer drug Posiphen into its primary metabolic products (+)-N1-norPosiphen, (+)-N8-norPosiphen and (+)-N1, N8-bisnorPosiphen, their inhibition of amyloid precursor protein, α-Synuclein synthesis, interleukin-1β release, and cholinergic action(Bentham Science Publishers, 2013) Yu, Qian-sheng; Reale, Marcella; Kamal, Mohammad A.; Holloway, Harold W.; Luo, Weiming; Sambamurti, Kumar; Ray, Balmiki; Lahiri, Debomoy K.; Rogers, Jack T.; Greig, Nigel H.; Department of Psychiatry, IU School of MedicineA major pathological hallmark of Alzheimer disease (AD) is the appearance in the brain of senile plaques that are primarily composed of aggregated forms of β-amyloid peptide (Aβ) that derive from amyloid precursor protein (APP). Posiphen (1) tartrate is an experimental AD drug in current clinical trials that reduces Aβ levels by lowering the rate of APP synthesis without toxicity. To support the clinical development of Posiphen (1) and elucidate its efficacy, its three major metabolic products, (+)-N1-norPosiphen (15), (+)-N8-norPosiphen (17) and (+)-N1, N8-bisnorPosiphen (11), were required in high chemical and optical purity. The efficient transformation of Posiphen (1) into these metabolic products, 15, 17 and 11, is described. The biological activity of these metabolites together with Posiphen (1) and its enantiomer, the AD drug candidate (-)-phenserine (2), was assessed against APP,α-synuclein and classical cholinergic targets. All the compounds potently inhibited the generation of APP and α-synuclein in neuronal cultures. In contrast, metabolites 11 and 15, and (-)-phenserine (2) but not Posiphen (1) or 17, possessed acetyl cholinesterase inhibitory action and no compounds bound either nicotinic or muscarinic receptors. As Posiphen (1) lowered CSF markers of inflammation in a recent clinical trial, the actions of 1 and 2 on proinflammatory cytokine interleukin (IL)-1β release human peripheral blood mononuclear cells was evaluated, and found to be potently inhibited by both agents.