Debomoy K Lahiri

Michigan State University, East Lansing, Michigan, United States

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Publications (251)1174.35 Total impact

  • Yokesh Balaraman, Debomoy K. Lahiri, John I. Nurnberger
    04/2015; 1(1):23-35. DOI:10.1159/000371886
  • Mythily Srinivasan, Debomoy K Lahiri
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    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.
    Expert Opinion on Therapeutic Targets 02/2015; 19(4):1-17. DOI:10.1517/14728222.2014.989834 · 4.90 Impact Factor
  • Debomoy K Lahiri
    Current Alzheimer research 01/2015; 12(2):96-9. · 3.80 Impact Factor
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    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.
    Current Alzheimer Research 12/2014; 12(1). DOI:10.2174/1567205012666141218140953 · 3.80 Impact Factor
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    Annals of Neurology 10/2014; 76(4). DOI:10.1002/ana.24254 · 11.91 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 10/2014; DOI:10.1016/j.jalz.2013.11.004 · 17.47 Impact Factor
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    Balmiki Ray, Nipun Chopra, Justin M Long, Debomoy K Lahiri
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    ABSTRACT: Background Culturing primary cortical neurons is an essential neuroscience technique. However, most cultures are derived from rodent brains and standard protocols for human brain cultures are sparse. Herein, we describe preparation, maintenance and major characteristics of a primary human mixed brain culture, including neurons, obtained from legally aborted fetal brain tissue. This approach employs standard materials and techniques used in the preparation of rodent neuron cultures, with critical modifications.ResultsThis culture has distinct differences from rodent cultures. Specifically, a significant numbers of cells in the human culture are derived from progenitor cells, and the yield and survival of the cells grossly depend on the presence of bFGF. In the presence of bFGF, this culture can be maintained for an extended period. Abundant productions of amyloid-ß, tau and proteins make this a powerful model for Alzheimer¿s research. The culture also produces glia and different sub-types of neurons.Conclusion We provide a well-characterized methodology for human mixed brain cultures useful to test therapeutic agents under various conditions, and to carry forward mechanistic and translational studies for several brain disorders.
    Molecular Brain 09/2014; 7(1):63. DOI:10.1186/s13041-014-0063-0 · 4.35 Impact Factor
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    ABSTRACT: 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.
    Journal of Psychiatric Research 08/2014; 59. DOI:10.1016/j.jpsychires.2014.07.011 · 4.09 Impact Factor
  • Scott E Counts, Debomoy K Lahiri
    Current Alzheimer Research 08/2014; 11(7):623-5. DOI:10.2174/156720501107140815102453 · 3.80 Impact Factor
  • D K Lahiri, Balmiki Ray
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    ABSTRACT: Alzheimer's disease (AD) is characterized by deleterious accumulation of amyloid-β (Aβ) peptide into senile plaque, neurofibrillary tangles formed from hyperphosphorylated tau protein, and loss of cholinergic synapses in the cerebral cortex. The deposition of Aβ-loaded plaques results in microglial activation and subsequent production of reactive oxygen species (ROS), including free radicals. Neurons in aging and AD brains are particularly vulnerable to ROS and other toxic stimuli. Therefore, agents that decrease the vulnerability of neurons against ROS may provide therapeuticvaluefor the treatment orprevention ofAD. In the present study, our goal was to test whether intravenous immunoglobulin (IVIG) treatment preserves and protects neurons from oxidative damage. We report that treatment withIVIG protects neuronal viability and synaptic proteins in primary rat hippocampal neurons. Further, we demonstrate the tolerability of IVIG treatment in the primary human fetal mixed brain cultures. Indeed, a high dose (20mg/mL) of IVIG treatment was well-tolerated by primary human brain cultures that exhibit a normal neuronal phenotype. Wealso observed a potent neuropreservatory effect of IVIG against ROS-mediated oxidative insults in these human fetalbrain cultures. These results suggest that IVIG treatment has great potential to preserve and protect primary human neuronal-enriched cultures andto potentially rescue dying neurons from oxidative insults. Therefore, our findings suggest that IVIG treatment may represent an important therapeutic agent for clinical trials designed to prevent and delay the onset of neurodegeneration as well as AD pathology.
    Current Alzheimer Research 08/2014; DOI:10.2174/1567205011666140812113851 · 3.80 Impact Factor
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    Debomoy K. Lahiri, Balmiki Ray
  • Kavita Shah, Debomoy K Lahiri
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    ABSTRACT: Cyclin dependent kinase-5 (Cdk5), a family member of the cyclin-dependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5.
    Journal of Cell Science 06/2014; 127(Pt 11):2391-2400. DOI:10.1242/jcs.147553 · 5.33 Impact Factor
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    ABSTRACT: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and retinal degeneration have been studied extensively and varying molecular mechanisms have been proposed for onset of such diseases. Although genetic analysis of these diseases has also been described, yet the mechanisms governing the extent of vulnerability to such diseases remains unresolved. Recent studies have, therefore, focused on the role of environmental exposure in progression of such diseases especially in the context of prenatal and postnatal life, explaining how molecular mechanisms mediate epigenetic changes leading to degenerative diseases. This review summarizes both the animal and human studies describing various environmental stimuli to which an individual or an animal is exposed during in-utero and postnatal period and mechanisms that promote neurodegeneration. The SNPs mediating gene environment interaction are also described. Further, preventive and therapeutic strategies are suggested for effective intervention.
    04/2014; 3:9. DOI:10.1186/2047-9158-3-9
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    ABSTRACT: Intravenous 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.
    Journal of Clinical Immunology 04/2014; 34(S1). DOI:10.1007/s10875-014-0020-9 · 2.65 Impact Factor
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    Nigel H Greig, Debomoy K Lahiri
    Current Alzheimer research 02/2014; 11(2):107-9. DOI:10.2174/156720501102140313162901 · 3.80 Impact Factor
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    ABSTRACT: Traumatic brain injury (TBI), either as an isolated injury or in conjunction with other injuries, is an increasingly common event. An estimated 1.7 million injuries occur within the USA each year and 10 million people are affected annually worldwide. Indeed, nearly one third (30.5%) of all injury-related deaths in the USA are associated with TBI, which will soon outpace many common diseases as the major cause of death and disability. Associated with a high morbidity and mortality and no specific therapeutic treatment, TBI has become a pressing public health and medical problem. The highest incidence of TBI occurs in young adults (15-24 years age) and in the elderly (≥75 years of age). Older individuals are particularly vulnerable to these types of injury, often associated with falls, and have shown increased mortality and worse functional outcome after lower initial injury severity. In addition, a new and growing form of TBI, blast injury, associated with the detonation of improvised explosive devices in the war theaters of Iraq and Afghanistan, are inflicting a wave of unique casualties of immediate impact to both military personnel and civilians, for which long-term consequences remain unknown and may potentially be catastrophic. The neuropathology underpinning head injury is becoming increasingly better understood. Depending on severity, TBI induces immediate neuropathologic effects that, for the mildest form, may be transient; however, with increasing severity, these injuries cause cumulative neural damage and degeneration. Even with mild TBI, which represents the majority of cases, a broad spectrum of neurologic deficits, including cognitive impairments, can manifest that may significantly influence quality of life. Further, TBI can act as a conduit to longer term neurodegenerative disorders. Prior studies of glucagon-like peptide-1 (GLP-1) and long-acting GLP-1 receptor agonists have demonstrated neurotrophic/neuroprotective activities across a broad spectrum of cellular and animal models of chronic neurodegenerative (Alzheimer's and Parkinson's diseases) and acute cerebrovascular (stroke) disorders. In view of the mechanisms underpinning these disorders as well as TBI, we review the literature and recent studies assessing GLP-1 receptor agonists as a potential treatment strategy for mild to moderate TBI.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 02/2014; 10(1S):S62-S75. DOI:10.1016/j.jalz.2013.12.011 · 17.47 Impact Factor

Publication Stats

9k Citations
1,174.35 Total Impact Points

Institutions

  • 2014
    • Michigan State University
      • Department of Translational Science and Molecular Medicine
      East Lansing, Michigan, United States
  • 2007–2014
    • University of Indianapolis
      Indianapolis, Indiana, United States
  • 1993–2014
    • Indiana University-Purdue University School of Medicine
      • • Psychiatry
      • • Medical and Molecular Genetics
      Indianapolis, Indiana, United States
  • 1991–2014
    • Indiana University-Purdue University Indianapolis
      • • Institute of Psychiatric Research
      • • Department of Psychiatry
      • • Department of Neurology
      Indianapolis, Indiana, United States
    • CUNY Graduate Center
      New York, New York, United States
  • 2013
    • Riley Hospital for Children
      Indianapolis, Indiana, United States
  • 2011
    • The Neurosciences Institute
      La Jolla, California, United States
  • 2010
    • Indian Institute of Toxicology Research
      • Division of Developmental Toxicology
      Lucknow, Uttar Pradesh, India
  • 2009
    • University of Southern California
      Los Angeles, California, United States
  • 2008–2009
    • University of Rhode Island
      • Department of Biomedical and Pharmaceutical Sciences
      Kingston, RI, United States
    • Universidad Autónoma de Madrid
      • Department of Medicine
      Madrid, Madrid, Spain
  • 2002–2006
    • National Institute on Aging
      • • Laboratory of Neurosciences (LNS)
      • • Drug Design and Development Section
      Baltimore, Maryland, United States
  • 2003
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 1998
    • University of Louisville
      • Department of Microbiology and Immunology
      Louisville, KY, United States
  • 1989
    • Icahn School of Medicine at Mount Sinai
      • Department of Psychiatry
      Borough of Manhattan, New York, United States