Targeting the α7 nicotinic acetylcholine receptor to prevent progressive dementia and improve cognition in adults with Down's syndrome

Prog Neuropsychopharmacol Biol Psychiatry. 2014 Oct 3;54:131-9. doi: 10.1016/j.pnpbp.2014.05.011. Epub 2014 May 24.

Abstract

As persons with Down's syndrome (DS) age into the third decade and beyond, they develop Alzheimer's disease (AD)-like histopathological changes in brain and may manifest progressive worsening of adaptive functions. Increasingly, persons with DS have near-normal to normal life spans; thus, it has become a therapeutic imperative to preserve adaptive functions and ability to live as independently as possible in the least restrictive environment throughout adulthood. Data suggest that these histopathological changes and worsening adaptive functions result, at least in part, from the binding of the amyloidogenic Aβ1-42 peptide to α7 nicotinic acetylcholine receptors (α7nAChRs) on the surface of neurons, which can lead to the internalization of the tightly-bound complex and cell lysis. Pharmacotherapeutic targeting of the α7nAChR may inhibit the creation of the Aβ1-42-α7nAChR complex, which has been observed both intraneuronally and as a component of the amyloid plaque seen in AD. Additionally, selective α7nAChR agonists may improve memory and cognition independently of their potential ability to attenuate the cytotoxicity of Aβ1-42 and retard the deposition of amyloid plaques in adults with DS. However, there are conflicting data supporting an antagonist strategy to improve cognition in the presence of elevated levels of Aβ amyloidogenic peptides, as well as to prevent emergence of pyramidal neuron hyperexcitability. A major challenge to the implementation of clinical trials of targeted α7nAChR interventions in adults with DS will be the ability to detect medication-induced changes in cognition in the context of intellectual disability. The Review will consider some of the current evidence supporting both the role of the Aβ1-42-α7nAChR complex in the pathogenesis of the AD-like histopathology in adult persons with DS, and pharmacotherapeutic interventions with α7nAChR agonists.

Keywords: Amyloid β-peptides; Down's syndrome; Intellectual disability; α(7) nicotinic acetylcholine receptor.

Publication types

  • Review

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Animals
  • Cognition / drug effects*
  • Cognition / physiology
  • Dementia / physiopathology
  • Dementia / prevention & control*
  • Down Syndrome / drug therapy*
  • Down Syndrome / physiopathology
  • Humans
  • Nootropic Agents / pharmacology
  • Nootropic Agents / therapeutic use
  • Peptide Fragments / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

  • Amyloid beta-Peptides
  • Nootropic Agents
  • Peptide Fragments
  • alpha7 Nicotinic Acetylcholine Receptor
  • amyloid beta-protein (1-42)