|
KMID : 0960920020010010006
|
|
Dementia and Neurocognitive Disorders
2002 Volume.1 No. 1 p.6 ~ p.12
|
|
|
Treatment of Alzheimer’s Disease-Nicotinic Receptors as a New Target
|
|
Nordberg Agneta
|
|
|
Abstract
|
|
|
|
Alzheimer’s disease is the most common form of dementia. The disease is accompanied by several distinct molecular events including formation and accumulation of beta amyloid(Aβ), hyperphosphorylation of tau proteins and neurochemical changes including neurotransmitter function. The neuronal nicotinic acetylcholine receptors(nAChRs) in the brain are important for functional processes, including cognitive and memory functions. The nAChRs acting as neuromodulators in communicative processes regulated by different neurotransmitters and show a relatively high abundance in human cortex, with a laminar distribution of the nChRs of superhigh to high, and low affinity in human cortex. Consistent losses of nAChRs of superhigh to high, and low affnity in human cortex. Consistent losses of nAChRs have been measured in vitro in autopsy brain tissue of the Alzheimer patients(AD), as well as in vivo by positron emisson tomography(PET). Measurement of the protein content of nAChRs showed reduced levels of the α4, α3, α7_nAChRs subtypes. The α4 and α3 mRNA levels are not changed in AD for at the translation and/or posttranslational level. The increased mRNA level of the α7 nAChR subtype in the hippocampus indicates that subunit specific changes in gene expression of the α7 nAChR might be associated with AD. PET studies have revealed deficits in nAChRs early in the course of AC disease, stressing the importance of nAChRs as a potential target for drug intervention. Different cholinesterase inhibitors are presently clinical used. The effect is mainly considered to be symptomatic although influcence on the disease progression cannot be exclued. Except for a direct inhibition of acetylcholinesterase and buturylchlinesterase a indirect effect via an allosteric site on the nicotinic receptor may improve the clinical outcome. The nAChR appears to mediate neuroprotective effects. We have recently found that longterm treatment with nicotine to APPsw trangenic mice sicnificantly reduce the Aβ amyloides in the brain. Further studies on neuroprotective mechanisms mediated via nAChR sbtypes are exciting new avenues.
|
|
|
KEYWORD
|
|
|
AD, human brain, Alzheimer’s disease, Treatment strategies, Neuronal nicotinic, receptor subtypes, PET ligands, Nicotinic agonists, Cholinesterase inhibitors
|
|
|
FullTexts / Linksout information
|
|
|
|
|
Listed journal information
|
|
|
|
|