Nicotinic receptor subtypes in human brain ageing, Alzheimer and Lewy body diseases.
Human brain ageing is associated with reductions in a variety of nicotinic receptors subtypes, whereas changes in age-related disorders including Alzheimer's disease or Parkinson's disease are more selective. In Alzheimer's disease, in the cortex there is a selective loss of the alpha4 (but not alpha3 or 7) subunit immunoreactivity and of nicotine or epibatidine binding but not alpha-bungarotoxin binding. Epibatidine binding is inversely correlated with clinical dementia ratings and with the level of Abeta1-42, but not related to plaque or tangle densities. In contrast, alpha-bungarotoxin binding is positively correlated with plaque densities in the entorhinal cortex. In human temporal cortex loss of acetylcholinesterase catalytic activity is positively correlated with decreased epibatidine binding and in a transgenic mouse model over expressing acetylcholinesterase, epibatidine binding is elevated. In Parkinson's disease, loss of striatal nicotine binding appears to occur early but is not associated with a loss of alpha4 subunit immunoreactivity. Tobacco use in normal elderly individuals is associated with increased alpha4 immunoreactivity in the cortex and lower densities of amyloid-beta plaques, and with greater numbers of dopaminergic neurons in the substantia nigra pars compacta. These findings indicate an early involvement of the alpha4 subunit in beta-amyloidosis but not in nigro-striatal dopaminergic degeneration.
Perry
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E
Department of Neuropathology, MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road, Newcastle, UK. e.k.perry@ncl.ac.uk
Martin-Ruiz
C
C
Lee
M
M
Griffiths
M
M
Johnson
M
M
Piggott
M
M
Haroutunian
V
V
Buxbaum
J D
JD
Nãsland
J
J
Davis
K
K
Gotti
C
C
Clementi
F
F
Tzartos
S
S
Cohen
O
O
Soreq
H
H
Jaros
E
E
Perry
R
R
Ballard
C
C
McKeith
I
I
Court
J
J
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000544:Alzheimer Disease / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009538:Nicotine / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; D009538:Nicotine; D000110:Acetylcholinesterase