Browsing by Author "Lahiri, Debomoy K."

Now showing 1 - 5 of 5
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    PublicationLetter
    A cardinal sin when researching neuropsin/KLK8: Thou shalt validate antibodies
    (Elsevier Inc., 2017) Lahiri, Debomoy K.; Konar, Arpita; Thakur, Mahendra K.; Maloney, Bryan
    [No abstract available]
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    PublicationArticle
    A serine protease KLK8 emerges as a regulator of regulators in memory: Microtubule protein dependent neuronal morphology and PKA-CREB signaling
    (Nature Publishing Group, 2018) Konar, Arpita; Kumar, Ashish; Maloney, Bryan; Lahiri, Debomoy K.; Thakur, Mahendra K.
    The multitude of molecular pathways underlying memory impairment in neurological disorders and aging-related disorders has been a major hurdle against therapeutic targeting. Over the years, neuronal growth promoting factors, intracellular kinases, and specific transcription factors, particularly cyclic AMP response element-binding protein (CREB), have emerged as crucial players of memory storage, and their disruption accompanies many cognitive disabilities. However, a molecular link that can influence these major players and can be a potential recovery target has been elusive. Recent reports suggest that extracellular cues at the synapses might evoke an intracellular signaling cascade and regulate memory function. Herein, we report novel function of an extracellular serine protease, kallikrein 8 (KLK8/Neuropsin) in regulating the expression of microtubule associated dendrite growth marker microtubule-associated protein (MAP2)c, dendrite architecture and protein kinase A (PKA)-CREB signaling. Both knockdown of KLK8 via siRNA transfection in mouse primary hippocampal neurons and via intra-hippocampal administration of KLK8 antisense oligonucleotides in vivo reduced expression of MAP2c, dendrite length, dendrite branching and spine density. The KLK8 mediated MAP2c deficiency in turn inactivated PKA and downstream transcription factor phosphorylated CREB (pCREB), leading to downregulation of memory-linked genes and consequent impaired memory consolidation. These findings revealed a protease associated novel pathway of memory impairment in which KLK8 may act as a "regulator of regulators", suggesting its exploration as an important therapeutic target of memory disorders. © 2018 The Author(s).
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    PublicationConference paper
    Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases
    (Blackwell Publishing Inc., 2005) Lahiri, Debomoy K.; Chen, De-Mao; Lahiri, Preeti; Bondy, Steve; Greig, Nigel H.
    The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid β peptides (Aβ), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Aβ, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Aβ peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms. © 2005 New York Academy of Sciences.
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    PublicationArticle
    M1 muscarinic receptor is a key target of neuroprotection, neuroregeneration and memory recovery by i-Extract from Withania somnifera
    (Nature Publishing Group, 2019) Konar, Arpita; Gupta, Richa; Shukla, Rajendra K.; Maloney, Bryan; Khanna, Vinay K.; Wadhwa, Renu; Lahiri, Debomoy K.; Thakur, Mahendra K.
    Memory loss is one of the most tragic symptoms of Alzheimer’s disease. Our laboratory has recently demonstrated that ‘i-Extract’ of Ashwagandha (Withania somnifera) restores memory loss in scopolamine (SC)-induced mice. The prime target of i-Extract is obscure. We hypothesize that i-Extract may primarily target muscarinic subtype acetylcholine receptors that regulate memory processes. The present study elucidates key target(s) of i-Extract via cellular, biochemical, and molecular techniques in a relevant amnesia mouse model and primary hippocampal neuronal cultures. Wild type Swiss albino mice were fed i-Extract, and hippocampal cells from naïve mice were treated with i-Extract, followed by muscarinic antagonist (dicyclomine) and agonist (pilocarpine) treatments. We measured dendritic formation and growth by immunocytochemistry, kallikrein 8 (KLK8) mRNA by reverse transcription polymerase chain reaction (RT-PCR), and levels of KLK8 and microtubule-associated protein 2, c isoform (MAP2c) proteins by western blotting. We performed muscarinic receptor radioligand binding. i-Extract stimulated an increase in dendrite growth markers, KLK8 and MAP2. Scopolamine-mediated reduction was significantly reversed by i-Extract in mouse cerebral cortex and hippocampus. Our study identified muscarinic receptor as a key target of i-Extract, providing mechanistic evidence for its clinical application in neurodegenerative cognitive disorders. © 2019, The Author(s).
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    PublicationConference paper
    Melatonin, metals, and gene expression: Implications in aging and neurodegenerative disorders
    (New York Academy of Sciences, 2004) Lahiri, Debomoy K.; Chen, Demao; Lahiri, Preeti; Rogers, Jack T.; Greig, Nigel H.; Bondy, Stephen
    Melatonin is a hormone secreted by the pineal gland, mostly in the dark period of the light/dark cycle, with corresponding fluctuations reflected in the plasma melatonin levels. This hormone plays a critical role in the regulation of various neural and endocrine processes that are synchronized with daily change in photoperiod. Abnormal melatonin levels are associated with metabolic disturbances and other disorders. Melatonin potentially plays an important role in aging, prolongation of life span, and health in the aged individual. It may exert a beneficial action on neurodegenerative conditions in those with debilitating diseases. It interacts with metals and, in some cases, neutralizes their toxic effects. Levels of melatonin decrease with aging in mice. Its dietary supplementation has recently been shown to result in a significant rise in levels of endogenous melatonin in serum as well as all other tissue samples tested. The effects of dietary melatonin have been studied in the brain of mice with regard to nitric oxide synthase, synaptic proteins, and amyloid β peptides (Aβ), which are involved in amyloid deposition and plaque formation in Alzheimer's disease (AD). Melatonin supplementation has no significant effect on cerebral cortical levels of nitric oxide synthase or synaptic proteins, such as synaptophysin and SNAP-25. Notably, however, elevated brain melatonin levels resulted in a significant reduction in levels of toxic cortical Aβ of both 40- and 42-aminoacid forms. Taken together, these results suggest that dietary melatonin supplementation may slow the neurodegenerative changes associated with brain aging and that the depletion of melatonin in the brain of aging mice may, in part, account for this adverse change. ©2004 New York Academy of Sciences.