High reelin expression can explain why the entorhinal cortex is a cradle for Alzheimer's disease

Abstract

The entorhinal cortex (EC) plays a crucial role in memory functions. Long before the clinical symptoms of Alzheimers 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. It was recently shown that in layer II neurons of the anterolateral entorhinal cortex (alECLII neurons), which are especially prone to display a very early increase in intracellular amounts of amyloid-{beta} peptide (A{beta}) and hyperphosphorylated tau protein (p-tau), the large glycoprotein reelin binds to A{beta}, suggesting that reelin functions as a sink for intracellular A{beta}. The expression of reelin is extraordinarily high in alECLII neurons compared to most other cortical neurons. Here, we show by computational modeling that, in a senescent physiology predisposing to frequent inflammation-driven A{beta}42 production bursts, the intracellular amount of A{beta}42-reelin complexes can accumulate to extraordinarily high levels in alECLII neurons compared to the vast majority of cortical neurons. This explains experimental data showing that intracellular accumulations of A{beta}42 positive material ranged from 20 to 80% of the total cytoplasmic volume in EC neurons from patients with sporadic AD. We also show that this extreme intracellular aggregation can cause the accumulation of detrimental hyperphosphorylated tau fragments. Thus, when exposed to recurrent AD-promoting stress, the exceptionally high expression of reelin in alECLII neurons appears to be instrumental in their early demise relative to other cortical neurons.