Neuronal phenotypes in human hippocampus and neocortex in late-onset Alzheimer's disease: protein expression of novel genes implicated in pathogenesis
Adams, Stephanie Lynn
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Genetic factors involved in late-onset Alzheimer’s disease (AD), affecting the majority of AD patients, are largely unknown. Genome-wide association studies implicated genes associated with increased risk of AD, including BIN1 (Bridging Integrator 1), and MSRB3 (methionine sulfoxide reductase-B3), also associated with low hippocampal volume. In an effort to find effective therapies, animal studies using intracerebralventricular administration of neurotrophic factor bone morphogenetic protein-9 (BMP9) decreased pathological burden and preserved cholinergic phenotype in AD mouse model hippocampus. To examine the potential role of BIN1, MSRB3, and ALK1, the BMP9 receptor, in human hippocampal AD-associated pathology, we examined their protein expression in postmortem human hippocampi using automated immunohistochemistry, and correlated the data with neuropathological reports and clinical dementia ratings. In elderly control subjects, BIN1 protein was expressed in white matter, glia, and neuropil along axons. CA1 quantitative analysis of BIN1 signal during AD progression revealed expression decreased in neuropil and increased in the cytoplasm of pyramidal neurons. The number of CA1 BIN1-immunoreactive pyramidal neurons correlated with the hippocampal CERAD neuritic plaque score while BIN1 neuropil signal was absent at neuritic plaque sites. MSRB3 was differentially expressed in hippocampal pyramidal layers. Controls exhibited MSRB3 signal as distinct but rare (≤2) puncta in CA1 pyramidal neuron somata. MSRB3 immunoreactivity in CA3 was found in the pyramidal layer neuropil. MSRB3 signal was also observed in rodent hippocampi where ultrastructural and immunohistofluorescent analysis revealed MSRB3 associates with synaptic vesicles (SV) and colocalizes with SV and mossy fiber markers respectively. In AD patients the population of CA1 pyramidal neurons with frequent (≥5), rather than rare, MSRB3-immunoreactive somatic puncta increased in comparison to controls and correlated positively with AD pathological hallmarks. Finally, cholinergic neurons of human and rodent basal forebrain were ALK1-immunoreactive. In healthy CA1, ALK1 was expressed prominently in neuropil and in GABAergic interneurons, while CA2, CA3, and CA4 showed ALK1-immunoreactive neuropil and pyramidal somata. The intensity of ALK1-immunoreactivity in CA3 decreased in moderate and late AD patients compared to non-AD subjects. These data show that neuronal, glial, and hippocampal subfield-specific changes in protein expression of potential AD modulators are associated with AD progression and its diagnostic hallmarks.