Browsing by Author "Lahiri, Debomoy K."

Now showing 1 - 10 of 88
  • Thumbnail Image
    Item
    Advances in Alzheimer therapy: understanding pharmacological approaches to the disease
    (Bentham Science Publishers, 2009-04) Martinez, Ana; Lahiri, Debomoy K.; Giacobini, Ezio; Greig, Nigel H.; Department of Psychiatry, IU School of Medicine
    Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy".
  • Thumbnail Image
    Item
    Advances in understanding Alzheimer's disease, and the contributions of current Alzheimer research: ten years on and beyond
    (Bentham Science Publishers, 2014-02) Greig, Nigel H.; Lahiri, Debomoy K.; Department of Psychiatry, IU School of Medicine
  • Thumbnail Image
    Item
    The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen
    (Springer Nature, 2011-03) Rogers, Jack T.; Mikkilineni, Sohan; Castelvetri, Ippolita Cantuti; Smith, Deborah H.; Huang, Xudong; Bandyopadhyay, Sanghamitra; Cahill, Catherine M.; Maccecchini, Maria L.; Lahiri, Debomoy K.; Greig, Nigel H.; Psychiatry, School of Medicine
    Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo.
  • Thumbnail Image
    Item
    Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease
    (Bentham Science, 2015) Baranello, Robert J.; Bharani, Krishna L.; Padmaraju, Vasudevaraju; Chopra, Nipun; Lahiri, Debomoy K.; Greig, Nigel H.; Pappolla, Miguel A.; Sambamurti, Kumar; Department of Psychiatry, IU School of Medicine
    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 ε4 allele of Apolipoprotein E (ApoE-ε4) 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 γ-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 Aβ degradation or clearance may play a key role in 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 Aβ turnover.
  • Thumbnail Image
    Item
    Amyloid-β precursor protein synthesis inhibitors for Alzheimer's disease treatment
    (Wiley, 2014-10) Greig, Nigel H.; Sambamurti, Kumar; Lahiri, Debomoy K.; Becker, Robert E.; Department of Psychiatry, IU School of Medicine
  • Thumbnail Image
    Item
    APPealing for a role in cellular iron efflux
    (American Society for Biochemistry and Molecular Biology, 2019-06-14) Lahiri, Debomoy K.; Maloney, Bryan; Wang, Ruizhi; Medical and Molecular Genetics, School of Medicine
  • Thumbnail Image
    Item
    APPlications of amyloid-β precursor protein metabolites in macrocephaly and autism spectrum disorder
    (Frontiers Media, 2023-09-20) Sokol, Deborah K.; Lahiri, Debomoy K.; Neurology, School of Medicine
    Metabolites of the Amyloid-β precursor protein (APP) proteolysis may underlie brain overgrowth in Autism Spectrum Disorder (ASD). We have found elevated APP metabolites (total APP, secreted (s) APPα, and α-secretase adamalysins in the plasma and brain tissue of children with ASD). In this review, we highlight several lines of evidence supporting APP metabolites’ potential contribution to macrocephaly in ASD. First, APP appears early in corticogenesis, placing APP in a prime position to accelerate growth in neurons and glia. APP metabolites are upregulated in neuroinflammation, another potential contributor to excessive brain growth in ASD. APP metabolites appear to directly affect translational signaling pathways, which have been linked to single gene forms of syndromic ASD (Fragile X Syndrome, PTEN, Tuberous Sclerosis Complex). Finally, APP metabolites, and microRNA, which regulates APP expression, may contribute to ASD brain overgrowth, particularly increased white matter, through ERK receptor activation on the PI3K/Akt/mTOR/Rho GTPase pathway, favoring myelination.
  • Thumbnail Image
    Item
    Are pulmonary fibrosis and Alzheimer's disease linked? Shared dysregulation of two miRNA species and downstream pathways accompany both disorders
    (American Society for Biochemistry and Molecular Biology, 2017-12-08) Lahiri, Debomoy K.; Maloney, Bryan; Greig, Nigel H.; Psychiatry, School of Medicine
  • Thumbnail Image
    Item
    BACE1 Gene Regulation: A Novel Drug Target in Alzheimer’s Disease
    (Office of the Vice Chancellor for Research, 2013-04-05) Bayon, Baindu L.; Bailey, Jason; Lahiri, Debomoy K.
    Alzheimer’s disease (AD) is the most common form of dementia in the elderly in the United States. AD is characterized by the presence of amyloid-β (Aβ) peptide plaques. Aberrant deposition is believed to result from the misregulation of the production or the clearance of Aβ. The rate-limiting step in Aβ production is the processing of amyloid- β precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). BACE1 could play a critical role in the development of AD and is a promising drug target. In this study, we aim to reduce BACE1 enzyme levels by reducing BACE1 gene expression. We previously analyzed the promoter activity of BACE1 and the 5’ untranslated region of BACE1 mRNA. The BACE1 promoter contains many transcription factor sites including SP1, MEF2, and STAT1, which have been shown to play a role in the regulation of BACE1 gene expression. Mithramycin A (MithA) has been previously shown to selectively inhibit SP1-mediated transcriptional activation. We expect inhibition of SP1 to lead to downregulation of BACE1 and decreased Aβ, providing a novel target for AD. We have tested several BACE1 promoter-deletion constructs by DNA transfection in human neuronal cultures, treatment with MithA, and performed luciferase reporter assays. In a neuroblastoma (NB) cell line, we observed the significant increase in luciferase reporter activity of two BACE1 plasmid constructs after treatment with MithA. Treatment also correlated with an increase in BACE1 protein expression and a decrease in APP expression. This suggests that the mechanism by which MithA influences the BACE1 promoter could be complex and or due to other transcription factor sites as well. Further experiments will include using differentiated NB cells and human primary fetal neurons, along with the use of other Sp1 inhibitors including tolfenamic acid to elucidate the regulation of APP and BACE1 promoters leading to lower Aβ levels.
  • Thumbnail Image
    Item
    Biological Hallmarks of Cancer in Alzheimer’s Disease
    (Elsevier, 2019-04-16) Nudelman, Kelly N. H.; McDonald, Brenna C.; Lahiri, Debomoy K.; Saykin, Andrew J.; Medical and Molecular Genetics, School of Medicine
    Although Alzheimer’s disease (AD) is an international health research priority for our aging population, little therapeutic progress has been made. This lack of progress may be partially attributable to disease heterogeneity. Previous studies have identified an inverse association of cancer and AD, suggesting that cancer history may be one source of AD heterogeneity. These findings are particularly interesting in light of the number of common risk factors and two-hit models hypothesized to commonly drive both diseases. We reviewed the ten hallmark biological alterations of cancer cells to investigate overlap with the AD literature and identified overlap of all ten hallmarks in AD, including: 1) potentially common underlying risk factors, such as increased inflammation, deregulated cellular energetics, and genome instability, 2) inversely regulated mechanisms, including cell death and evading growth suppressors, and 3) functions with more complex, pleiotropic mechanisms, some of which may be stage-dependent in AD, such as cell adhesion/contact inhibition and angiogenesis. Additionally, we discuss the recent observation of a biological link between cancer and AD neuropathology. Finally, we address the therapeutic implications of this topic. The significant overlap of functional pathways and molecules between these diseases, some similarly and some oppositely regulated or functioning in each disease, supports the need for more research to elucidate cancer-related AD genetic and functional heterogeneity, with the aims of better understanding AD risk mediators, as well as further exploring the potential for some types of drug repurposing towards AD therapeutic development.