High reelin expression may explain why a subgroup of entorhinal cortex neurons functions as an initial nucleation site of Alzheimer's disease.

The entorhinal cortex (EC) plays a crucial role in memory functions. Long before the clinical symptoms of Alzheimer's disease (AD) emerge, it has already undergone significant degeneration, making it a primary site for the onset of the disease. The reasons for this remain elusive. Layer II (LII) neurons of the anterolateral EC are especially prone to display a very early increase in intracellular amounts of amyloid-β peptide (Aβ) and hyperphosphorylated tau protein (p-tau). The expression of the large glycoprotein reelin is extraordinarily high in ECLII neurons compared to most other cortical neurons and proximity ligation assay data and other immunohistochemical data strongly support the notion that reelin binds to Aβ in these neurons. Here, based on the premise that reelin may function as a sink for intracellular Aβ, we show by computational modeling that, in a senescent physiology predisposing to frequent inflammation-driven Aβ42 production bursts over a decades-long period, the intracellular amount of Aβ42-reelin complexes can accumulate to extraordinarily high levels in anterolaterally positioned LII neurons compared to the vast majority of cortical neurons. This is consistent with experimental data showing that intracellular accumulations of Aβ42 positive material ranged from 20 to 80% of total soma volume in EC neurons from patients with idiopathic AD. Based on known tau protein biology, we also show that this extreme intracellular aggregation that overloads the lysosomal degradation machinery, manifesting chronic homeostatic dysregulation, can lead to the production of p-tau fragments prone to aggregation. Together, our findings may contribute to the resolution of why the EC is so strongly associated with the very early etiology of AD.