Abstract Projection neurons in the anterolateral part of entorhinal cortex layer II (alEC LII) are the predominant cortical site for hyperphosphorylation of tau (p-tau) and formation of neurofibrillary tangles (NFTs) in brains of subjects with early-stage Alzheimer’s Disease (AD). A majority of alEC LII-neurons are unique among cortical excitatory neurons by expressing the protein reelin (Re+). In AD patients, and a rat model for AD overexpression mutated human APP, these Re+ excitatory projection-neurons are prone to accumulate intracellular amyloid-β (iAβ). Biochemical pathways that involve reelin-signaling regulate levels of p-tau, and iAβ has been shown to impair such reelin-signaling. We therefore used the rat model and set out to assess whether accumulation of iAβ in Re+ alEC LII projection neurons relates to the fact that these neurons express reelin. Here we show that in Re+ alEC LII-neurons, reelin and iAβ42 engage in a direct protein-protein interaction, and that microRNA-mediated lowering of reelin-levels in these neurons leads to a concomitant reduction of non-fibrillar iAβ ranging across three levels of aggregation. Our experiments are carried out several months before plaque pathology emerges in the rat model, and the reduction of iAβ occurs without any substantial associated changes in human APP-levels. We propose a model positioning reelin in a sequence of changes in functional pathways in Re+ alEC LII-neurons, explaining the region and neuron-specific initiation of AD pathology. Significance Anterolateral entorhinal cortex layer II (EC LII) neurons are the predominant cortical site for hyperphosphorylation of tau (p-tau) and formation of neurofibrillary tangles (NFTs) in brains of subjects with early-stage Alzheimer’s disease (AD). The same neurons are prone to very early accumulation of non-fibrillary forms of amyloid-β in the context of AD, and are unique among cortical excitatory neurons by expressing the protein reelin. We show that in such alEC LII-neurons, reelin and iAβ42 engage in a direct protein-protein interaction, and that selectively lowering levels of reelin leads to a concomitant reduction of non-fibrillar Aβ. We propose a model positioning reelin in a sequence of changes in functional pathways in reelin-expressing EC LII neurons, explaining the region and neuron specific initiation of AD.
