Intraneuronal binding of amyloid beta with reelin-Implications for the onset of Alzheimer's disease

Numerous studies of the human brain supported by experimental results from rodent and cell models point to a central role for intracellular amyloid beta (A beta) in the onset of Alzheimer's disease (AD). In a rat model used to study AD, it was recently shown that in layer II neurons of the anteriolateral entorhinal cortex expressing high levels of the glycoprotein reelin (Re+alECLII neurons), reelin and A beta engage in a direct protein-protein interaction. If reelin functions as a sink for intracellular A beta and if the binding to reelin makes A beta physiologically inert, it implies that reelin can prevent the neuron from being exposed to the harmful effects typically associated with increased levels of oligomeric A beta. Considering that reelin expression is extraordinarily high in Re+alECLII neurons compared to most other cortical neurons, such a protective role appears to be very difficult to reconcile with the fact that this subset of ECLII neurons is clearly a major cradle for the onset of AD. Here, we show that this conundrum can be resolved if Re+alECLII neurons have a higher maximum production capacity of A beta than neurons expressing low levels of reelin, and we provide a rationale for why this difference has evolved.