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

Abstract

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 α7 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-β-peptide plaques, neurofibrillary tangles) and then focuses on more recent efforts of pharmacologic intervention in AD, specifically targeted to the α7 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 α7 AChRs and are aimed at unleashing the factors that hinder agonist-mediated, α7 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.

The Effect of Thymoquinone, α7 Receptor Agonist and α7 Receptor Allosteric Modulator on the Cerebral Cortex in Experimentally Induced Alzheimer's Disease in Relation to MSCs Activation

“…So we could suggest that the agonist and the modulator together interfere with α7 nAChR /Aβ binding thus leaving the receptor free for signaling and hence the desirable effect at histopathological level. This suggestion is supported by the demonstration that the PAM allosteric modulators aimed at unleashing the factors that hinder agonist mediated α7 nAChR channel activation (1). …”

“…Pathognomonic hallmarks of the disease include the development of beta –amyloid (Aβ) senile plaques and deposits of neurofibrillary tangles. Thus, compounds that could interfere with Aβ formation may be potential therapeutic agents for treatment of AD (1). …”

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

“…33 Nevertheless, the mechanism of action of α7 nAChRs on AD appears to be very complex, 34 since both neuroprotection 35 and neurotoxicity 36 may be influenced by α7 nAChR activity. And, given the multifactorial nature of AD, the same might happen at the level of compounds used at present in its treatment.…”

The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

“…This review will discuss the recent advances and pitfalls of these ligands and evaluate the potential of a 7 agonists for the treatment of schizophrenia, based on searches of PubMed and SciFinder (from January 1, 2000 to March 1, 2015) for English-language papers, and clinical trial registries. The use of a 7 agonists for the treatment of Alzheimer's disease (AD) was recently reviewed [28].…”