a-582941 and Alzheimer-Disease

Alzheimer disease (AD) is a progressive neurodegenerative disorder with associated memory loss, spatial disorientation, and other psychiatric problems. Cholinergic system dysfunction is an early and salient feature of AD, and enhancing cholinergic signaling with acetylcholinesterase inhibitors is currently the primary strategy for improving cognition. The beneficial effects of acetylcholinesterase inhibitors, however, are typically short-lived and accompanied by adverse effects. Recent evidence suggests that activating α7 nicotinic acetylcholine receptors (α7 nAChR) may facilitate the specific modulation of brain cholinergic signaling, leading to cognitive enhancement and possibly to amelioration of AD pathologic findings. In the present study, we determined the effect of long-term treatment with the selective α7 nAChR agonist A-582941 in aged 3xTg-AD mice with robust AD-like pathology, which is particularly significant not only because this is the only mouse model that co-develops amyloid plaques and neurofibrillary tangles but also because it enabled us to explore whether A-582941 is able to restore brain function after the severe damage associated with AD. Analysis of β-amyloid deposits, tau phosphorylation, and inflammatory cells revealed that, overall, pathologic findings were unchanged. Rather, α7 nAChR activation induced expression of c-Fos and brain-derived neurotrophic factor and phosphorylation of cyclic adenosine monophosphate response element binding and neurotrophic tyrosine receptor kinase type 2. More important, A-582941 completely restored cognition in aged 3xTg-AD mice to the level of that in age-matched nontransgenic mice. These novel findings indicate that activating α7 nAChR is a promising treatment for cognitive impairment in AD.

Topics: Aging; alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Cognition; Humans; Inflammation; Male; Memory; Mice; Mice, Transgenic; Neurofibrillary Tangles; Nootropic Agents; Phosphorylation; Plaque, Amyloid; Pyridazines; Pyrroles; tau Proteins

The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and has generated recent interest as a potential drug target for treating neurodegenerative disorders such as Alzheimer's disease (AD). The property of Ca(2+) permeation associated with alpha7 nAChR agonism may lead to Ca(2+)-dependent intracellular signaling that contribute to the procognitive and neuroprotective effects that have been described with this pharmacology. In this study, we investigated whether alpha7 nAChR agonism leads to increased phosphorylation of the inhibitory regulating amino acid residue Ser-9 on GSK3beta, a major kinase responsible for tau hyperphosphorylation in AD neuropathology. Immunohistochemical analysis revealed that the selective alpha7 agonist A-582941 increased S(9)-GSK3beta phosphorylation in mouse cingulate cortex and hippocampus that was not observed in alpha7 nAChR knock-out mice. A-582941 steady state exposure through continuous (2 wk) infusion also increased S(9)-GSK3beta phosphorylation in the hippocampus of Tg2576 (APP), as well as wild-type mice. Moreover, A-582941 continuous infusion decreased phosphorylation of tau in hippocampal CA3 Mossy fibers and spinal motoneurons in a hypothermia-induced tau hyperphosphorylation mouse model and AD double transgenic APP/tau mouse line, respectively. These studies demonstrate that inactivation of GSK3beta may be associated with alpha7 nAChR-induced signaling leading to attenuated tau hyperphosphorylation, raising the intriguing possibility that alpha7 nAChR agonism may have disease modifying benefit in the treatment of tauopathies, in particular AD.

Topics: alpha7 Nicotinic Acetylcholine Receptor; Alzheimer Disease; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Immunohistochemistry; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Pyridazines; Pyrroles; Receptors, Nicotinic; Signal Transduction; tau Proteins