title: Development of Precision Small-Molecule Proneurotrophic Therapies for Neurodegenerative Diseases.
abstract: Age-related neurodegenerative diseases, such as Alzheimer's disease, will represent one of the largest future burdens on worldwide healthcare systems due to the increasing proportion of elderly in our society. As deficiencies in neurotrophins are implicated in the pathogenesis of many age-related neurodegenerative disorders, it is reasonable to consider that global neurotrophin resistance may also become a major healthcare threat. Central nervous system networks are effectively maintained through aging by neuroprotective and neuroplasticity signaling mechanisms which are predominantly controlled by neurotrophin receptor signaling. Neurotrophin receptors are single pass receptor tyrosine kinases that form dimeric structures upon ligand binding to initiate cellular signaling events that control many protective and plasticity-related pathways. Declining functionality of the neurotrophin ligand-receptor system is considered one of the hallmarks of neuropathological aging. Therefore, it is imperative to develop effective therapeutic strategies to contend with this significant issue. While the therapeutic applications of cognate ligands for neurotrophin receptors are limited, the development of nonpeptidergic, small-molecule ligands can overcome these limitations, and productively regulate this important receptor system with beneficial effects. Using our advanced knowledge of the high-dimensionality complexity of receptor systems, the future generation of precision medicines targeting these systems will be an attainable goal.
authors.affiliation: Translational Neurobiology Group, University of Antwerp, Antwerpen, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Janssens
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore MD United States.
authors.forename: D
authors.initials: D
authors.lastname: Lu
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore MD United States.
authors.forename: B
authors.initials: B
authors.lastname: Ni
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore MD United States.
authors.forename: W
authors.initials: W
authors.lastname: Chadwick
authors.affiliation: Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore MD United States.
authors.forename: S
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: Translational Neurobiology Group, University of Antwerp, Antwerpen, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Azmi
authors.affiliation: Translational Neurobiology Group, University of Antwerp, Antwerpen, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Etienne
authors.affiliation: Translational Neurobiology Group, University of Antwerp, Antwerpen, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Jushaj
authors.affiliation: Translational Neurobiology Group, University of Antwerp, Antwerpen, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: van Gastel
authors.affiliation: Metabolism Unit, National Institute on Aging, National Institutes of Health, Baltimore MD United States.
authors.forename: B
authors.initials: B
authors.lastname: Martin
authors.affiliation: Translational Neurobiology Group, University of Antwerp, Antwerpen, Belgium; Receptor Pharmacology Unit, National Institute on Aging, National Institutes of Health, Baltimore MD United States. Electronic address: stuart.maudsley@molgen.vib-ua.be.
authors.forename: S
authors.initials: S
authors.lastname: Maudsley
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D019281:Dimerization; D015195:Drug Design; D015507:Drugs, Investigational / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D017475:Receptors, Nerve Growth Factor / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015507:Drugs, Investigational; D008024:Ligands; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D011498:Protein Precursors; D017475:Receptors, Nerve Growth Factor
keywords: Aging; Dementia; Neurodegeneration; Neurotrophin; Precision; Receptor; Tyrosine kinase