Reduction in 18FNifene Binding, a PET imaging Probe for α4β2 Nicotinic acetylcholinergic receptors in Hippocampus-Subiculum of postmortem human Alzheimer's disease brain

• Published in: Brain research p. 149600
• Main Authors: Karim, Fariha, Ngo, Allyson, Danh, Tram B, Delaney, Brooke A, Liang, Christopher, Serrano, Geidy E, Beach, Thomas G, Mukherjee, Jogeshwar
• Format: Journal Article
• Language: English
• Published: 26.03.2025
• ISSN: 1872-6240; 1872-6240
• DOI: 10.1016/j.brainres.2025.149600

Nicotinic acetylcholinergic receptors (nAChRs), including the α4β2* subtype are involved in cognition, learning and memory and may be adversely affected in Alzheimer's disease (AD). In our efforts to consider translational use of [18F]nifene PET in AD, we report quantitative autoradiographic evaluation of α4β2* nAChRs using hippocampus-subiculum (HP-SUB) from cognitively normal (CN) and AD subjects. Brain slices were incubated in [18F]nifene for α4β2* nAChRs and adjacent sections were tested with [18F]flotaza for Aβ plaques and [125I]IPPI for tau. Anti-Aβ and anti-tau immunostaining were carried out on adjacent slices. Regions of interest were drawn and binding of [18F]nifene, [18F]flotaza and [125I]IPPI were quantified.All CN subjects exhibited significant [18F]nifene binding in the HP-SUB regions. Average [18F]nifene ratios of SUB to HP was 1.9, suggesting higher α4β2* nAChRs in the SUB versus HP regions. [18F]nifene binding did not change with aging in the female subjects, while the male subjects exhibited a weak positive correlation. There was a significant decrease in the binding of [18F]nifene in AD subjects compared to CN. Braak stage comparisons showed a decrease of [18F]nifene in stages V and VI, while [18F]flotaza and [125I]IPPI increased significantly. A negative correlation was observed between [18F]nifene vs [18F]flotaza and [18F]nifene vs [125I]IPPI across Braak stages I-VI. These findings suggest that α4β2* nAChR availability was effectively measured by [18F]nifene in the HP-SUB and was adversely affected by the presence of Aβ plaques and tau.Nicotinic acetylcholinergic receptors (nAChRs), including the α4β2* subtype are involved in cognition, learning and memory and may be adversely affected in Alzheimer's disease (AD). In our efforts to consider translational use of [18F]nifene PET in AD, we report quantitative autoradiographic evaluation of α4β2* nAChRs using hippocampus-subiculum (HP-SUB) from cognitively normal (CN) and AD subjects. Brain slices were incubated in [18F]nifene for α4β2* nAChRs and adjacent sections were tested with [18F]flotaza for Aβ plaques and [125I]IPPI for tau. Anti-Aβ and anti-tau immunostaining were carried out on adjacent slices. Regions of interest were drawn and binding of [18F]nifene, [18F]flotaza and [125I]IPPI were quantified.All CN subjects exhibited significant [18F]nifene binding in the HP-SUB regions. Average [18F]nifene ratios of SUB to HP was 1.9, suggesting higher α4β2* nAChRs in the SUB versus HP regions. [18F]nifene binding did not change with aging in the female subjects, while the male subjects exhibited a weak positive correlation. There was a significant decrease in the binding of [18F]nifene in AD subjects compared to CN. Braak stage comparisons showed a decrease of [18F]nifene in stages V and VI, while [18F]flotaza and [125I]IPPI increased significantly. A negative correlation was observed between [18F]nifene vs [18F]flotaza and [18F]nifene vs [125I]IPPI across Braak stages I-VI. These findings suggest that α4β2* nAChR availability was effectively measured by [18F]nifene in the HP-SUB and was adversely affected by the presence of Aβ plaques and tau.