Region specific reduction of neurogranin immunostaining in the hippocampus of Alzheimer’s disease brains

Abstract

AbstractBackgroundNeurogranin (Ng) is a post‐synaptic protein involved in formation of long‐term potentials, and thus plays an important role in learning and memory. The concentration of Ng is increased in the cerebrospinal fluid (CSF) of people with Alzheimer’s disease (AD), and CSF Ng is considered to be a biomarker for synaptic dysfunction in AD. The expression of Ng protein in the human brain and its association with AD pathology, however, are less well studied.MethodUsing immunohistochemical detection methods we investigated the protein expression of Ng, beta‐amyloid (Aβ) and hyperphosphorylated paired helical filament tau (phospho‐tau; ptau) in the post‐mortem hippocampus from 12 AD patients and 12 cognitively unaffected controls (NC). We compared the number of positively stained cells (Ng, ptau) or plaques (Aβ) in the hippocampal sub‐regions (dentate gyrus, Cornu Ammonis (CA) fields 1‐3) from the 2 groups. Donor samples with intermediate AD (i.e., Braak stage III‐IV) or NC (Braak 0‐I/II) were analyzed using Image Pro Premier automated image analysis software (version 10.01). The data were normalized to the number of cells or clusters/mm2 and analyzed using a one‐way ANOVA. Using a test of circularity (Cir = (4*A)/Pi*MaxFeret2), we further investigated morphological differences in the Ng positive neurons by measuring the Ng expression in the apical dendrite of pyramidal neurons.ResultThere was a 40% reduction of Ng immunopositive neurons in AD compared to NC in the CA3(N = 24;p = 0.0003) and in the CA1(N = 24;p = 0.014) hippocampal sub‐regions. Ng positive cells did not change significantly in AD compared to NC in the other hippocampal regions. Additionally, we showed that CA1 region, Ng was localized mainly in the neuronal cell soma of AD donors, while its expression extended into the apical dendrites of NC donors (N = 24;p = 0.006). In AD, Ng immunostaining negatively correlated with ptau immunopositive neurofibrillary tangles (r = ‐0.70;p = 0.04)ConclusionSelective loss of Ng immunostaining in certain subregions of the hippocampus suggests that synaptic damage in AD maybe 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 to AD.