Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer's disease

• Published in: Neurobiology of disease Vol. 93; pp. 172 - 183
• Main Authors: Kobro-Flatmoen, Asgeir, Nagelhus, Anne, Witter, Menno P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2016; Elsevier
• Subjects: Alzheimer Disease - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid-β; Animals; Cell Adhesion Molecules, Neuronal - metabolism; Cytoplasm - metabolism; Entorhinal Cortex - metabolism; Entorhinal Cortex - pathology; Extracellular Matrix Proteins - metabolism; Hippocampal formation; Hippocampus - metabolism; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurology; Neurons - metabolism; Neuropathology; Parahippocampal region; Plaque, Amyloid - metabolism; Rats, Transgenic; Serine Endopeptidases - metabolism; Parahippocampal region; Amyloid-β; Neurodegeneration; Neuropathology; Hippocampal formation; hippocampal formation; parahippocampal region; amyloid-β; neuropathology
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2016.05.012

The onset of Alzheimer's disease (AD) is associated with subtle pathological changes including increased intracellular expression of amyloid-β (Aβ). A structure affected particularly early in the course of AD is the entorhinal cortex, where neuronal death in layer II is observed already at initial stages. Neurons in EC-layer II, particularly those that express the protein Reelin, give rise to projections to the hippocampal dentate gyrus and this projection shows severe loss of synaptic contacts during early-stage AD. Given this anatomical specificity, we sought to determine whether increased intracellular expression of Aβ is selectively associated with Reelin-immunoreactive neurons in layer II of the entorhinal cortex. Here we report that in a transgenic rat model, which mimics the onset and distribution of extracellular amyloid deposits seen in human AD subjects, expression of intracellular Aβ in entorhinal layer II selectively occurs in Reelin-immunoreactive neurons during the early, pre-plaque stage. This Reelin-Aβ association is also present in human subjects with AD-related pathological changes, even in early disease stages. These findings strongly indicate that Reelin-immunoreactive neurons in entorhinal layer II play a crucial role during the initial stages of AD, and may therefore lead to refined hypotheses concerning the origin of this devastating condition. •Reelin entorhinal layer II neurons selectively express intracellular Aβ in TG-rats.•This layer II Reelin-Aβ association already occurs in the pre-plaque stage.•This entorhinal Reelin-Aβ association is present also in early AD human subjects.•Reelin-immunoreactive neurons may play a crucial role in the initial stages of AD.