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

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 A beta(1-42) peptide to alpha(7) nicotinic acetylcholine receptors (alpha(7)nAChRs) on the surface of neurons, which can lead to the internalization of the tightly-bound complex and cell lysis. Pharmacotherapeutic targeting of the alpha(7)nAChR may inhibit the creation of the A beta(1-42)-alpha(7)nAChR complex, which has been observed both intraneuronally and as a component of the amyloid plaque seen in AD. Additionally, selective alpha(7)nAChR agonists may improve memory and cognition independently of their potential ability to attenuate the cytotoxicity of A beta(1-42) 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 A beta amyloidogenic peptides, as well as to prevent emergence of pyramidal neuron hyperexcitability. A major challenge to the implementation of clinical trials of targeted alpha(7)nAChR 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 A beta(1-42)-alpha(7)nAChR complex in the pathogenesis of the AD-like histopathology in adult persons with DS, and pharmacotherapeutic interventions with alpha(7)nAChR agonists. (C) 2014 Elsevier Inc. All rights reserved.