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      Epilepsy, amyloid-β, and D1 dopamine receptors: a possible pathogenetic link?

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          Abstract

          Experimental and clinical observations indicate that amyloid-β1-42 (Aβ1-42) peptide not only represents a major actor in neurodegenerative mechanisms but also induce hyperexcitation in individual neurons and neural circuits. In this abnormal excitability, possibly leading to seizures, the D1 dopamine (DA) receptors may play a role. Cerebrospinal fluid levels of Aβ1-42 were measured in patients with late-onset epilepsy of unknown etiology. Moreover, the effect of amyloid peptide on the hippocampal epileptic threshold and synaptic plasticity and its link to D1 receptor function were tested in experimental mouse model of cerebral amyloidosis and in acute model of Aβ1-42-induced neurotoxicity. Among 272 evaluated epileptic patients, aged >55 years, 35 suffered from late-onset epilepsy of unknown etiology. In these subjects, cerebrospinal fluid Aβ1-42 levels were measured. The effects of Aβ1-42, amyloid oligomers, and D1 receptor modulation on epileptic threshold were analyzed by electrophysiological recordings in the dentate gyrus of mice hippocampal slices. We found that Aβ1-42 levels were significantly decreased in cerebrospinal fluid of patients with late-onset epilepsy of unknown etiology with respect to controls suggesting the cerebral deposition of this peptide in these patients. Aβ1-42 enhanced epileptic activity in mice through a mechanism involving increased surface expression of D1 receptor, and this effect was mimicked by D1 receptor stimulation and blocked by SCH 23390, a D1 receptor antagonist. Aβ1-42 may contribute to the pathophysiology of late-onset epilepsy of unknown origin. Our preclinical findings indicate that the D1 receptor is involved in mediating the epileptic effects of Aβ1-42. This novel link between Aβ1-42 and D1 receptor signaling might represent a potential therapeutic target.

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          Author and article information

          Journal
          Neurobiol. Aging
          Neurobiology of aging
          Elsevier BV
          1558-1497
          0197-4580
          Dec 2016
          : 48
          Affiliations
          [1 ] Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy. Electronic address: cinzia.costa@unipg.it.
          [2 ] Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
          [3 ] Laboratory of Molecular Neuroscience, Department of Medicine, Campus Bio-Medico University, Rome, Italy; Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
          [4 ] Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy; Department of Experimental Medicine, University of Perugia, Perugia, Italy.
          [5 ] Neurophysiopathology Unit, Department of Systems Medicine, Sleep and Epilepsy Medicine Centre, Tor Vergata University and Hospital, Rome, Italy.
          [6 ] Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
          [7 ] Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy; Neurophysiopathology Unit, Department of Systems Medicine, Sleep and Epilepsy Medicine Centre, Tor Vergata University and Hospital, Rome, Italy.
          [8 ] Clinica Neurologica, Department of Medicine, University of Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy; Department of Experimental Neurosciences, "Istituto di Ricovero e Cura a Carattere Scientifico", IRCCS Santa Lucia Foundation, Rome, Italy.
          Article
          S0197-4580(16)30203-2
          10.1016/j.neurobiolaging.2016.08.025
          27701029
          ac5b1b2e-e34a-4ec2-a625-e119911eedfb
          History

          Alzheimer's disease,Aβ(1–42) oligomers,D1 dopamine receptor,Epileptic threshold,Seizures,Transgenic mice

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