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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.

journal_name

Brain Res Bull

journal_title

Brain research bulletin

authors

Kroker KS,Moreth J,Kussmaul L,Rast G,Rosenbrock H

doi

10.1016/j.brainresbull.2013.04.006

subject

Has Abstract

pub_date

2013-07-01 00:00:00

pages

28-38

eissn

0361-9230

issn

1873-2747

pii

S0361-9230(13)00072-5

journal_volume

pub_type

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Restoring long-term potentiation impaired by amyloid-beta oligomers: comparison of an acetylcholinesterase inhibitior and selective neuronal nicotinic receptor agonists.