4.5 Article

Targeting Brain α7 Nicotinic Acetylcholine Receptors in Alzheimer's Disease: Rationale and Current Status

期刊

CNS DRUGS
卷 28, 期 11, 页码 975-987

出版社

ADIS INT LTD
DOI: 10.1007/s40263-014-0201-3

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资金

  1. FONCYT [PICT 2011-0604]
  2. Ministry of Science and Technology
  3. PIP from the National Scientific and Technical Research Council of Argentina (CONICET) [112-201101-01023]

向作者/读者索取更多资源

Alzheimer's disease (AD) is the most common form of dementia among older persons. Pathognomonic hallmarks of the disease include the development of amyloid senile plaques and deposits of neurofibrillary tangles. These changes occur in the brain long before the clinical manifestations of AD (cognitive impairment in particular) become apparent. Nicotinic acetylcholine receptors (AChRs), particularly the alpha 7 subtype, are highly expressed in brain regions relevant to cognitive and memory functions and involved in the processing of sensory information. There is strong evidence that implicates the participation of AChRs in AD. This review briefly introduces current strategies addressing the pathophysiologic findings (amyloid-beta-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the alpha 7 AChR. Whereas cholinesterase inhibitors such as donepezil, galantamine, or rivastigmine, together with the non-competitive N-methyl-D-aspartate receptor antagonist memantine are at the forefront of present-day clinical intervention for AD, new insights into AChR molecular pharmacology are bringing other drugs, directed at AChRs, to center stage. Among these are the positive allosteric modulators that selectively target alpha 7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, alpha 7 AChR channel activation. This calls for more detailed knowledge of the distribution, functional properties, and involvement of AChRs in various signaling cascades-together with the corresponding abnormalities in all these properties-to be able to engineer strategies in drug design and evaluate the therapeutic possibilities of new compounds targeting this class of neurotransmitter receptors.

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