Alpha4 but not alpha3 and alpha7 nicotinic acetylcholine receptor subunits are lost from the temporal cortex in Alzheimer's disease.
Neuronal nicotinic acetylcholine receptors labelled with tritiated agonists are reduced in the cerebral cortex in Alzheimer's disease (AD), but to date it has not been demonstrated which nicotinic receptor subunits contribute to this deficit. In the present study, autopsy tissue from the temporal cortex of 14 AD cases and 15 age-matched control subjects was compared using immunoblotting with antibodies against recombinant peptides specific for alpha3, alpha4, and alpha7 subunits, in conjunction with [3H]epibatidine binding. Antibodies to alpha3, alpha4, and alpha7 produced one major band on western blots at 59, 51, and 57 kDa, respectively. [3H]Epibatidine binding and alpha4-like immunoreactivity (using antibodies against the extracellular domain and cytoplasmic loop of the alpha4 subunit) were reduced in AD cases compared with control subjects (p < 0.02) and with a subgroup of control subjects (n = 9) who did not smoke prior to death (p < 0.05) for the former two parameters. [3H]Epibatidine binding and cytoplasmic alpha4-like immunoreactivity were significantly elevated in a subgroup of control subjects (n = 4) known to have smoked prior to death (p < 0.05). There were no significant changes in alpha3- or alpha7-like immunoreactivity associated with AD or tobacco use. The selective involvement of alpha4 has implications for understanding the role of nicotinic receptors in AD and potential therapeutic targets.
Martin-Ruiz
C M
CM
MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, England, UK.
Court
J A
JA
Molnar
E
E
Lee
M
M
Gotti
C
C
Mamalaki
A
A
Tsouloufis
T
T
Tzartos
S
S
Ballard
C
C
Perry
R H
RH
Perry
E K
EK
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009447:Neuroblastoma; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D011725:Pyridines / Q000493:pharmacokinetics; D011869:Radioligand Assay; D011978:Receptors, Nicotinic / Q000302:isolation & purification / Q000378:metabolism*; D012016:Reference Values; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D014316:Tritium; D014407:Tumor Cells, Cultured; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000906:Antibodies; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; D014316:Tritium; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; C082748:epibatidine