Karim Fariha, Ngo Allyson, Danh Tram B, Delaney Brooke A, Liang Christopher, Serrano Geidy E, Beach Thomas G, Mukherjee Jogeshwar
Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697, USA.
Banner Sun Health Research Institute, Sun City, AZ 85351, USA.
Brain Res. 2025 Jun 15;1857:149600. doi: 10.1016/j.brainres.2025.149600. Epub 2025 Mar 26.
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 [F]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 [F]nifene for α4β2* nAChRs and adjacent sections were tested with [F]flotaza for Aβ plaques and [I]IPPI for tau. Anti-Aβ and anti-tau immunostaining were carried out on adjacent slices. Regions of interest were drawn and binding of [F]nifene, [F]flotaza and [I]IPPI were quantified.All CN subjects exhibited significant [F]nifene binding in the HP-SUB regions. Average [F]nifene ratios of SUB to HP was 1.9, suggesting higher α4β2* nAChRs in the SUB versus HP regions. [F]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 [F]nifene in AD subjects compared to CN. Braak stage comparisons showed a decrease of [F]nifene in stages V and VI, while [F]flotaza and [I]IPPI increased significantly. A negative correlation was observed between [F]nifene vs [F]flotaza and [F]nifene vs [I]IPPI across Braak stages I-VI. These findings suggest that α4β2* nAChR availability was effectively measured by [F]nifene in the HP-SUB and was adversely affected by the presence of Aβ plaques and tau.
包括α4β2亚型在内的烟碱型乙酰胆碱受体（nAChRs）参与认知、学习和记忆过程，在阿尔茨海默病（AD）中可能会受到不利影响。在我们考虑将[F]尼非尼PET用于AD的转化应用时，我们报告了使用认知正常（CN）和AD受试者的海马-下托（HP-SUB）对α4β2 nAChRs进行定量放射自显影评估。将脑切片与用于α4β2* nAChRs的[F]尼非尼一起孵育，并用用于Aβ斑块的[F]氟他唑和用于tau的[I]IPPI对相邻切片进行检测。在相邻切片上进行抗Aβ和抗tau免疫染色。绘制感兴趣区域并对[F]尼非尼、[F]氟他唑和[I]IPPI的结合进行定量。所有CN受试者在HP-SUB区域均表现出显著的[F]尼非尼结合。下托与海马的平均[F]尼非尼比值为1.9，表明下托区域的α4β2* nAChRs高于海马区域。女性受试者中[F]尼非尼结合随年龄增长无变化，而男性受试者表现出弱正相关。与CN相比，AD受试者中[F]尼非尼的结合显著降低。Braak分期比较显示，在V期和VI期[F]尼非尼减少，而[F]氟他唑和[I]IPPI显著增加。在Braak I-VI期，观察到[F]尼非尼与[F]氟他唑以及[F]尼非尼与[I]IPPI之间呈负相关。这些发现表明，[F]尼非尼可有效测量HP-SUB中α4β2* nAChR的可用性，且其受到Aβ斑块和tau的不利影响。
