Lowering levels of reelin in entorhinal cortex layer II-neurons results in lowered levels of intracellular amyloid-β.
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 Alzheimers 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-{beta} (iA{beta}). Biochemical pathways that involve reelin-signaling regulate levels of p-tau, and iA{beta} has been shown to impair such reelin-signaling. We therefore used the rat model and set out to assess whether accumulation of iA{beta} 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 iA{beta}42 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 iA{beta} 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 iA{beta} 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. SignificanceAnterolateral 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 Alzheimers disease (AD). The same neurons are prone to very early accumulation of non-fibrillary forms of amyloid-{beta} 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 iA{beta}42 engage in a direct protein-protein interaction, and that selectively lowering levels of reelin leads to a concomitant reduction of non-fibrillar A{beta}. 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.