Progressive worsening of adaptive functions in Down syndrome may be mediated by the complexing of soluble Abeta peptides with the alpha 7 nicotinic acetylcholine receptor: therapeutic implications.
In persons with Down syndrome, soluble Abeta peptides, which result from the processing of the amyloid precursor protein, appear in the brain decades before the extracellular deposition of neuritic plaques. These soluble amyloidogenic peptides accumulate intraneuronally and can be secreted extracellularly. Their appearance has been reported in the brains of fetuses with Down syndrome. The extra gene dosage effect associated with trisomy 21 results in abnormalities of the processing of amyloid precursor protein in persons with Down syndrome. Abeta peptides, especially Abeta1-42, have been shown to form tight complexes with the alpha7 nicotinic acetylcholine receptor, interfering with transduction of the acetylcholine signal by this nicotinic receptor subtype. Furthermore, the selective binding of Abeta peptides by this nicotinic acetylcholine receptor subtype is associated with cytotoxicity. The alpha7 nicotinic acetylcholine receptor has unique electrophysiologic properties and plays a prominent role in normal psychophysiologic processes (eg, sensory inhibition) and cognition. In persons with Down syndrome there is a decrease in the ability to perform instrumental activities of daily living that worsen with aging. The progressive worsening of adaptive functions and cognition in persons with Down syndrome may be, at least in part, mediated by interference with this receptor by soluble Abeta peptides. In view of this complex formed by soluble Abeta peptides and the alpha7 nicotinic acetylcholine receptor, cholinergic interventions that have been developed for Alzheimer disease, including selective nicotinic ones, should be explored in Down syndrome. Ideally, selective cholinergic interventions would slow the progression of the worsening of adaptive function and emergence of dementia in persons with Down syndrome.
Deutsch
Stephen I
SI
Mental Health Service Line, VISN5, Department of Veterans Affairs Medical Center, 50 Irving Street NW, Washington, DC 20422, USA. Stephen.Deutsch@va.med.gov
Rosse
Richard B
RB
Mastropaolo
John
J
Chilton
Melissa
M
D000203:Activities of Daily Living; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004314:Down Syndrome / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; C579167:Chrna7 protein, human; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42)