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The nicotinic α7 receptor is highly expressed within
the brain and has limited peripheral expression (e.g.,
macrophages, ganglionic neurons). Selective nicotinic
α7 agonists have been shown to increase cholinergic
neurotransmission in a brain region-specific manner. Thus,
it is hypothesized that α7 agonists may contribute to
symptomatic treatment of Alzheimer disease through
cholinergic mechanisms and have a better safety profile than
observed with current therapies (Kem, 2000).
In addition to neurodegeneration, the brains of Alzheimer
disease patients display an abnormal accumulation of amyloid
plaques and accumulations of abnormal tau filaments as
neurofibrillary tangles. Amyloid plaques are insoluble
aggregates of protein that are toxic to neurons. The major
constituent of these plaques is the protein β amyloid.
Preclinical data from several laboratories suggests that the
amyloid protein from which these plaques are formed disrupts
the function of the nicotinic α7 receptor. Furthermore,
the most vulnerable neurons appear to be those that
abundantly express the nicotinic α7 receptor, and
internalization of amyloid-β1-42 (Aβ1-42) appears
to be facilitated by the high-affinity binding of
Aβ1-42 to the nicotinic α7 receptor on neuronal
cell surfaces (D’Andrea and Nagele, 2005). Therefore, the
nicotinic α7 receptor is a potentially important
therapeutic target for disease modification treatment.
Stimulation of nicotinic α7 receptors via agonist
administration protects neurons from degeneration induced by
Aβ1-42, further bolstering the idea that reduced
nicotinic α7 receptor signaling is a mediator of
age-related and Alzheimer’s-dependent cognitive decline
(D’Andrea and Nagele 2005). Drugs that activate nicotinic
α7 receptors would theoretically interfere with the
neurotoxic effects of Aβ1-42 and prevent the
pathophysiological and cognitive decline of Alzheimer’s
patients.
EVP-6124 has demonstrated improved learning and memory
function in a small Phase II clinical trial (See ARF
related news story and EnVivo
ICAD 2009 Poster).
Also see related Alzforum News story posted 5 November
2010. Experimental
Drug Sensitizes Receptor, Boosts Cognition
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