Debomoy K Lahiri

University of Indianapolis, Indianapolis, Indiana, United States

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Publications (372)

  • Craig A Erickson · Logan K Wink · Bayon Baindu · [...] · Debomoy K. Lahiri
    [Show abstract] [Hide abstract] ABSTRACT: Angelman Syndrome is a rare neurodevelopmental disorder associated with significant developmental and communication delays, high risk for epilepsy, motor dysfunction, and a characteristic behavioral profile. While Angelman Syndrome is known to be associated with the loss of maternal expression of the ubiquitin-protein ligase E3A gene, the molecular sequelae of this loss remain to be fully understood. Amyloid precursor protein (APP) is involved in neuronal development and APP dysregulation has been implicated in the pathophysiology of other developmental disorders including fragile X syndrome and idiopathic autism. APP dysregulation has been noted in preclinical model of chromosome 15q13 duplication, a disorder whose genetic abnormality results in duplication of the region that is epigenetically silenced in Angelman Syndrome. In this duplication model, APP levels have been shown to be significantly reduced leading to the hypothesis that enhanced ubiquitin-protein ligase E3A expression may be associated with this phenomena. We tested the hypothesis that ubiquitin-protein ligase E3A regulates APP protein levels by comparing peripheral APP and APP derivative levels in humans with Angelman Syndrome to those with neurotypical development. We report that APP total, APP alpha (sAPPα) and A Beta 40 and 42 are elevated in the plasma of humans with Angelman Syndrome compared to neurotypical matched human samples. Additionally, we found that elevations in APP total and sAPPα correlated positively with peripheral brain derived neurotrophic factor levels previously reported in this same patient cohort. Our pilot report on APP protein levels in Angelman Syndrome warrants additional exploration and may provide a molecular target of treatment for the disorder. © 2016 Wiley Periodicals, Inc.
    Article · Jun 2016 · American Journal of Medical Genetics Part A
  • Bryan Maloney · Debomoy K Lahiri
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease and other idiopathic dementias are associated with epigenetic transformations. These transformations connect the environment and genes to pathogenesis, and have led to the investigation of epigenetic-based therapeutic targes for the treatment of these diseases. Epigenetic changes occur over time in response to environmental effects. The epigenome-based latent early-life associated regulation (LEARn) hypothetical model indicates that accumulated environmental hits produce latent epigenetic changes. These hits can alter biochemical pathways until a pathological threshold is reached, which appears clinically as the onset of dementia. The hypotheses posed by LEARn are testable via longitudinal epigenome-wide, envirome-wide, and exposome-wide association studies (LEWAS) of the genome, epigenome, and environment. We posit that the LEWAS design could lead to effective prevention and treatments by identifying potential therapeutic strategies. Epigenetic evidence suggests that dementia is not a suddenly occurring and sharply delineated state, but rather a gradual change in crucial cellular pathways, that transforms an otherwise healthy state, as a result of neurodegeneration, to a dysfunctional state. Evidence from epigenetics could lead to ways to detect, prevent, and reverse such processes before clinical dementia.
    Article · Jun 2016 · The Lancet Neurology
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    Balmiki Ray · Deborah K. Sokol · Bryan Maloney · Debomoy K. Lahiri
    [Show abstract] [Hide abstract] ABSTRACT: Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are developmental disorders. No validated blood-based biomarkers exist for either, which impedes bench-to-bedside approaches. Amyloid-β (Aβ) precursor protein (APP) and metabolites are usually associated with Alzheimer’s disease (AD). APP cleavage by α-secretase produces potentially neurotrophic secreted APPα (sAPPα) and the P3 peptide fragment. β-site APP cleaving enzyme (BACE1) cleavage produces secreted APPβ (sAPPβ) and intact Aβ. Excess Aβ is potentially neurotoxic and can lead to atrophy of brain regions such as amygdala in AD. By contrast, amygdala is enlarged in ASD but not FXS. We previously reported elevated levels of sAPPα in ASD and FXS vs. controls. We now report elevated plasma Aβ and total APP levels in FXS compared to both ASD and typically developing controls, and elevated levels of sAPPα in ASD and FXS vs. controls. By contrast, plasma and brain sAPPβ and Aβ were lower in ASD vs. controls but elevated in FXS plasma vs. controls. We also detected age-dependent increase in an α-secretase in ASD brains. We report a novel mechanistic difference in APP pathways between ASD (processing) and FXS (expression) leading to distinct APP metabolite profiles in these two disorders. These novel, distinctive biochemical differences between ASD and FXS pave the way for blood-based biomarkers for ASD and FXS.
    Full-text Article · May 2016 · Scientific Reports
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    Balmiki Ray · Deborah K. Sokol · Bryan Maloney · Debomoy K. Lahiri
    Full-text Dataset · May 2016
  • Parul Bali · Debomoy K Lahiri · Avijit Banik · [...] · Akshay Anand
    [Show abstract] [Hide abstract] ABSTRACT: Alzheimer's disease (AD) is one of the common causes of dementia. Despite several decades of serious research in AD there is no standard disease modifying therapy available. Stem cells hold immense potential to regenerate tissue systems and are studied in a number of brain-related disorders. For various untreatable neurodegenerative disorders, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) (current-approved drugs provide only symptomatic relief), stem cell therapy holds a great promise and provides a great research opportunity. Here we review several stem cell transplantation studies with reference to both preclinical and clinical approaches. We focus on different sources of stem cells in a number of animal models and on molecular mechanisms involved in possible treatment of neurodegenerative disorders. The clinical studies reviewed suggest safety efficacy and translational potential of stem cell therapy. The therapeutic outcome of stem cell transplantation has been promising in many studies but no unifying hypothesis exists for an underlying mechanism. Some studies reported paracrine effects exerted by these cells via release of neurotrophic factors, while other studies reported immunomodulatory effects by transplanted cells. There are also reports supporting stem cell transplantation causing endogenous cell proliferation or replacement of diseased cells at the site of degeneration. In animal models of AD, stem cell transplantation is also believed to increase expression of synaptic proteins. A number of stem cell transplantation studies point out great potential for this novel approach in preventing or halting several neurodegenerative diseases. The current challenge is to clearly define the molecular mechanism by which stem cells operate and the extent of actual contribution by the exogenous and/or endogenous cells in the rescue of disease.
    Article · Mar 2016 · Current Alzheimer research
  • Debomoy K Lahiri · Bryan Maloney · Baindu L Bayon · [...] · John I Nurnberger
    [Show abstract] [Hide abstract] ABSTRACT: The origin of idiopathic diseases is still poorly understood. The latent early-life associated regulation (LEARn) model unites environmental exposures and gene expression while providing a mechanistic underpinning for later-occurring disorders. We propose that this process can occur across generations via transgenerational LEARn (tLEARn). In tLEARn, each person is a 'unit' accumulating preclinical or subclinical 'hits' as in the original LEARn model. These changes can then be epigenomically passed along to offspring. Transgenerational accumulation of 'hits' determines a sporadic disease state. Few significant transgenerational hits would accompany conception or gestation of most people, but these may suffice to 'prime' someone to respond to later-life hits. Hits need not produce symptoms or microphenotypes to have a transgenerational effect. Testing tLEARn requires longitudinal approaches. A recently proposed longitudinal epigenome/envirome-wide association study would unite genetic sequence, epigenomic markers, environmental exposures, patient personal history taken at multiple time points and family history.
    Article · Mar 2016 · Epigenomics
  • Kavita Shah · Debomoy K Lahiri
    [Show abstract] [Hide abstract] ABSTRACT: Cdk5, a cyclin-dependent kinase family member, is a global orchestrator of neuronal cytoskeletal dynamics. During embryogenesis, Cdk5 is indispensable for brain development. In adults, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation, drug addiction, pain signaling, and long-term behavior changes through long-term potentiation and long-term depression, all of which rely on rapid alterations in the cytoskeleton. Cdk5 activity becomes deregulated in various brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, attention-deficit hyperactivity disorder, epilepsy, schizophrenia, and ischemic stroke; these all result in profound remodeling of the neuronal cytoskeleton. This Commentary specifically focuses on the pleiotropic contribution of Cdk5 in regulating neuronal microtubule remodeling. Because the vast majority of the physiological substrates of Cdk5 are associated with the neuronal cytoskeleton, our emphasis is on the Cdk5 substrates, such as CRMP2, stathmin, drebrin, dixdc1, axin, MAP2, MAP1B, doublecortin, kinesin-5, and tau, that have allowed to unravel the molecular mechanisms through which Cdk5 exerts its divergent roles in regulating neuronal microtubule dynamics, both in healthy and disease states.
    Article · Mar 2016 · Molecular Neurobiology
  • Yue Huang · Debomoy Lahiri
    Article · Feb 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Stroke is the world’s leading cause of physiological disability, but there are currently no available agents that can be delivered early after stroke to enhance recovery. Daidzein, a soy isoflavone, is a clinically approved agent that has a neuroprotective effect in vitro, and it promotes axon growth in an animal model of optic nerve crush. The current study investigates the efficacy of daidzein on neuroprotection and functional recovery in a clinically relevant mouse model of stroke recovery. In light of the fact that cholesterols are essential lipid substrates in injury-induced synaptic remodeling, we found that daidzein enhanced the cholesterol homeostasis genetic program, including Lxr and downstream transporters, Apoe, Abca1, and Abcg1 genes in vitro. Daidzein also elevated the cholesterol homeostasis genes in the poststroke brain with Apoe, the highest expressing transporter, but did not affect infarct volume or hemispheric swelling. Despite the absence of neuroprotection, daidzein improved motor/gait function in chronic stroke and elevated synaptophysin expression. However, the daidzein-enhanced functional benefits and synaptophysin expression were abolished in Apoe-knock-out mice, suggesting the importance of daidzein-induced ApoE upregulation in fostering stroke recovery. Dissociation between daidzein-induced functional benefits and the absence of neuroprotection further suggest the presence of nonoverlapping mechanisms underlying recovery processes versus acute pathology. With its known safety in humans, early and chronic use of daidzein aimed at augmenting ApoE may serve as a novel, translatable strategy to promote functional recovery in stroke patients without adverse acute effect.
    Full-text Article · Nov 2015 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
  • [Show abstract] [Hide abstract] ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the fourth leading cause of death in the United States and most common cause of adult-onset dementia. The major hallmarks of AD are the formation of senile amyloid plaques made of beta amyloid and neurofibrillary tangles (NFT) which are primarily composed of phosphorylated tau protein. Although numerous agents have been considered as providing protection against AD, identification of potential agents with neuroprotective ability is limited. Thioflavin T has been used in the past to stain amyloid beta plaques in brain. In this study, Thioflavin T (ThT) and vehicle (infant formula) were administered orally by gavage to transgenic (B6C3 APP PS1; AD-Tg) mice beginning at 4 months age and continuing until sacrifice at 9 months of age at 40mg/kg dose. The number of amyloid plaques was reduced dramatically by ThT treatment in both male and female transgenic mice compared to those in control mice. Additionally, GFAP and Amylo-Glo labeling suggest that astrocytic hypertrophy is minimized in ThT-treated animals. Similarly, CD68 labeling, which detects activated microglia, along with Amylo-Glo labeling, suggests that microglial activation is significantly less in ThT-treated mice. Both Aβ-40 and Aβ-42 concentrations in blood rose significantly in the ThT-treated animals suggesting that ThT may inhibit the deposition, degradation, and/or clearance of Aβ plaques in brain.
    Article · Oct 2015 · Current Alzheimer Research
  • [Show abstract] [Hide abstract] ABSTRACT: Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.
    Article · Sep 2015 · Journal of Alzheimer's disease: JAD
  • D Sokol · D Lahiri · B Maloney · C Ho
    Article · Sep 2015 · Archives of Clinical Neuropsychology
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    Becker RE · Seeman MV · Nigel H Greig · Debomoy K Lahiri
    [Show abstract] [Hide abstract] ABSTRACT: Drug development for psychiatric disorders has almost ground to a halt. Some newer drugs are better tolerated or safer than older ones, but none is more effective. Years of failure in preventing or delaying the onset of illness, ameliorating symptoms, lowering suicide rates, or improving quality of life has put the commercial investments that had previously funded drug development at risk. To promote the development of psychiatric drugs with greater efficacy, we need to improve the way we bring potentially beneficial drugs to market. We need to acknowledge, as has been done in other specialties, that people differ in their response to drugs. Psychiatric drug research needs to be grounded in a better understanding of molecular brain mechanisms, neural circuits, and their relations to clinical disease. With this understanding, drugs need to be more precisely directed at specific brain targets. In psychiatric drug development, government, industry, regulatory bodies, and academia should realign to ensure medical science is used in the best interests of patients. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text Article · Aug 2015 · The Lancet Psychiatry
  • Article · Jul 2015
  • Debomoy K. Lahiri · Bryan Maloney · Justin Long · [...] · Balmiki Ray
    Article · Jul 2015
  • Debomoy K Lahiri
    Article · Jun 2015 · Current Aging Science
  • Debomoy K Lahiri
    Article · May 2015 · Current Alzheimer research
  • Yokesh Balaraman · Debomoy K. Lahiri · John I. Nurnberger
    [Show abstract] [Hide abstract] ABSTRACT: Recent advances in genome-wide association studies are pointing towards a major role for voltage-gated ion channels in neuropsychiatric disorders and, in particular, bipolar disorder (BD). The phenotype of BD is complex, with symptoms during mood episodes and deficits persisting between episodes. We have tried to elucidate the common neurobiological mechanisms associated with ion channel signaling in order to provide a new perspective on the clinical symptoms and possible endophenotypes seen in BD patients. We propose a model in which the multiple variants in genes coding for ion channel proteins would perturb motivational circuits, synaptic plasticity, myelination, hypothalamic-pituitary-adrenal axis function, circadian neuronal rhythms, and energy regulation. These changes in neurobiological mechanisms would manifest in endophenotypes of aberrant reward processing, white matter hyperintensities, deficits in executive function, altered frontolimbic connectivity, increased amygdala activity, increased melatonin suppression, decreased REM latency, and aberrant myo-inositol/ATP shuttling. The endophenotypes result in behaviors of poor impulse control, motivational changes, cognitive deficits, abnormal stress response, sleep disturbances, and energy changes involving different neurobiological process domains. The hypothesis is that these disturbances start with altered neural circuitry during development, following which multiple environmental triggers may disrupt the neuronal excitability balance through an activity-dependent molecular process, resulting in clinical mood episodes.
    Article · Apr 2015
  • Mythily Srinivasan · Debomoy K Lahiri
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Advances in molecular pathogenesis suggest that the chronic inflammation is a shared mechanism in the initiation and progression of multiple neurodegenerative diseases with diverse clinical manifestations such as Alzheimer's disease (AD) and Multiple sclerosis (MS). Restricted cell renewal and regenerative capacity make the neural tissues extremely vulnerable to the uncontrolled inflammatory process leading to irreversible tissue damage. Areas covered: A predominant consequence of increased inflammatory signaling is the upregulation of the transcription factor, NF-κB with subsequent neuroprotective or deleterious effects depending on the strength of the signal and the type of NF-κB dimers activated. We discuss the interplay between neuroinflammation and neurodegeneration keeping in focus NF-κB signaling as the point of convergence of multiple pathways associated with the development of the neurodegenerative pathologies, AD and MS. Expert opinion: Considerable interest exists in developing efficient NF-κB inhibitors for neurodegenerative diseases. The review includes an overview of natural compounds and rationally designed agents that inhibit NF-κB and mediate neuroprotection in AD and MS. The key chemical moieties of the natural and the synthetic compounds provide efficient leads for the development of effective small molecule inhibitors that selectively target NF-κB activation; this would result in the desired benefit to risk therapeutic effects.
    Article · Feb 2015 · Expert Opinion on Therapeutic Targets
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    [Show abstract] [Hide abstract] ABSTRACT: Amyloid-β proteins(Aβ) of 42 (Aβ42)and 40 aa (Aβ40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP),Presenilin-1 (PS1), Presenilin-2 (PS2),Adamalysin10,and other genetic risk factors for sporadic AD such as the γ4 allele of Apolipoprotein E (ApoE-γ4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by β -site APP cleaving enzyme (BACE1)and β-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42.However, the vast majority of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβdegradation or clearance may play a key rolein AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aβturnover.
    Full-text Article · Dec 2014 · Current Alzheimer Research

Publication Stats

13k Citations


  • 2006-2014
    • University of Indianapolis
      Indianapolis, Indiana, United States
  • 2009
    • University of Rhode Island
      • Department of Biomedical and Pharmaceutical Sciences
      Kingston, RI, United States
  • 2008
    • Universidad Autónoma de Madrid
      • Department of Medicine
      Madrid, Madrid, Spain
  • 2007
    • University of Kuopio
      Kuopio, Northern Savo, Finland
  • 2002-2005
    • National Institute on Aging
      • • Drug Design and Development Section
      • • Laboratory of Neurosciences (LNS)
      Baltimore, Maryland, United States
  • 2004
    • University of Florence
      Florens, Tuscany, Italy
  • 2003
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 1991-2002
    • Indiana University-Purdue University Indianapolis
      • • Department of Psychiatry
      • • Institute of Psychiatric Research
      Indianapolis, Indiana, United States
  • 2000
    • Harvard University
      Cambridge, Massachusetts, United States