Reduction of neurogranin immunostaining in the hippocampus of post‐mortem brain of Alzheimer’s disease

Abstract

AbstractBackgroundNeurogranin (Ng) is a post‐synaptic protein involved in formation of long‐term potential. It plays an important role in learning and memory. The concentration of Ng is increased in the cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), and CSF Ng is considered to be a biomarker for synaptic dysfunction in AD. In contrast, the expression of Ng protein in the human brain and its association with AD pathology are less well studied.MethodUsing immunohistochemical detection methods, we investigated the protein expression of Ng, beta‐amyloid (Aβ) and hyperphosphorylated tau (AT8) in the post‐mortem hippocampus from four AD patients and four normal controls (NC). We quantitively compared the number of Ng positively stained cells in the hippocampal sub‐regions (dentate gyrus, CA3, CA2 and CA1) in post‐mortem donors with intermediate AD (i.e., Braak stage III‐IV) to NC (Braak 0) using Image Pro Premier automated image analysis software. The data was normalized to the number of Ng cells/mm2 and analyzed using a one‐way ANOVA. The AT8 and Aβ were scored using a scale that ranged from 0‐3; based on the number of immunopositive structures identified per mm2. The Ng data was correlated to the AT8 and Aβ using the Pearson’s correlation.ResultWe showed that Ng was localized mainly in neuronal cell soma and dendritic processes of the hippocampus of AD and NC donors. On average there was a 30% reduction (p<0.05) of Ng immunopositive neurons in the dentate gyrus, CA2 and CA1 hippocampal sub‐regions in cases of AD compared to that of NC. Ng positive cells did not significantly change in the CA3 hippocampal region in cases with AD when compared to NC. In cases with AD the reduction of Ng immunostaining was correlated with increased AT8 immunopositive neurofibrillary tangles (r=‐ 0.80; p<0.05), but not with Aβ plaques.ConclusionLoss of Ng immunostaining in CA1, CA2 and dentate gyrus confirms that synaptic damage in AD is a region‐specific event. The mechanism underlying such regional synaptic damage and the changes in Ng expression will be key in understanding the selective vulnerability of brain regions and systems to AD.