title: Restoring long-term potentiation impaired by amyloid-beta oligomers: comparison of an acetylcholinesterase inhibitior and selective neuronal nicotinic receptor agonists.
abstract: As nicotinic acetylcholine receptor (nAChR) agonists directly address cholinergic neurotransmission with potential impact on glutamatergic function, they are considered as potential new symptomatic treatment options for Alzheimer's disease compared to the indirectly operating acetylcholinesterase inhibitors such as the current gold standard donepezil. In order to evaluate the therapeutic value of nAChR activation to ameliorate cognitive dysfunction, a direct comparison between α4β2, α7 nAChR agonists, and donepezil was performed on the level of an ex vivo experimental model of impaired memory formation. First, we demonstrated that amyloid beta (Aβ)42 oligomers, which are believed to be the synaptotoxic Aβ-species causally involved in the pathophysiology of Alzheimer's disease, have a detrimental effect on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices, a widely used cellular model of learning and memory. Second, we investigated the potential of donepezil, the α4β2 nAChR agonist TC-1827 and the α7 nAChR partial agonist SSR180711 to reverse Aβ42 oligomer induced LTP impairment. Donepezil showed only a slight reversal of Aβ42 oligomer induced impairment of early LTP, and had no effect on Aβ42 oligomer induced impairment of late LTP. The same was demonstrated for the α4β2 nAChR agonist TC-1827. In contrast, the α7 nAChR partial agonist SSR180711 completely rescued early as well as late LTP impaired by Aβ42 oligomers. As activating α7 nAChRs was found to be most efficacious in restoring Aβ42 oligomer induced LTP deficits, targeting α7 nAChRs might represent a powerful alternative approach for symptomatic treatment of AD.
authors: Boehringer Ingelheim Pharma GmbH & Co KG, Dept. of CNS Diseases Research, Birkendorfer Strasse 65, 88397 Biberach, Germany. katja.kroker@boehringer-ingelheim.com
authors: Katja S
authors: KS
authors: Kroker
authors: Jens
authors: J
authors: Moreth
authors: Lothar
authors: L
authors: Kussmaul
authors: Georg
authors: G
authors: Rast
authors: Holger
authors: H
authors: Rosenbrock
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D006624:Hippocampus / Q000187:drug effects; D007189:Indans / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002800:Cholinesterase Inhibitors; D007189:Indans; D018722:Nicotinic Agonists; D010880:Piperidines; D011978:Receptors, Nicotinic; C516833:SSR180711; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D000077265:Donepezil; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase inhibitor; Alzheimer's disease; Amyloid-β oligomer; Donepezil; LTP; Nicotinic acetylcholine receptor