Neuronal Nicotinic Receptor Deficits in Alzheimer Patients with the Swedish Amyloid Precursor Protein 670/671 Mutation

Abstract : The influence of β‐amyloid on cholinergic neurotransmission was studied by measuring alterations in nicotinic acetylcholine receptors (nAChRs) in autopsy brain tissue from subjects carrying the Swedish amyloid precursor protein (APP) 670/671 mutation. Significant reductions in numbers of nAChRs were observed in various cortical regions of the Swedish 670/671 APP mutation family subjects (‐73 to ‐87%) as well as in sporadic Alzheimer's disease (AD) cases (‐37 to ‐57%) using the nicotinic agonists ³H]epibatidine and ³H]nicotine, which bind with high affinity to both α3 and α4 and to α4 nAChR subtypes, respectively. Saturation binding studies with ³epibatidine revealed two binding sites in the parietal cortex of AD subjects and controls. A significant decrease in B_max (‐82%) for the high‐affinity site was observed in APP 670/671 subjects with no change in K_D compared with controls (0.018 nM APP 670/671 ; 0.036 nM control). The highest load of neuronal plaques (NPs) was observed in the parietal cortex of APP 670/671 brains, whereas the number of ³H]nicotine binding sites was less impaired compared with other cortical brain regions. Except for a positive significant correlation between the number of ³H]nicotine binding sites and number of NPs in the parietal cortex, no strict correlation was observed between nAChR deficits and the presence of NPs and neurofibrillary tangles, suggesting that these different processes may be closely related but not strictly dependent on each other.