Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease

Abstract

AbstractIt was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimer’s disease (AD)), the glycoprotein reelin and intracellular amyloid-β(Aβ) engage in a direct protein–protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric Aβin the onset of AD. If reelin functions as a sink for intracellular Aβand if the binding to reelin makes Aβphysiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric Aβ. Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of Aβthan neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of Aβin ECLII neurons may in a senescent Aβ-inducing physiology predispose these neurons to initiate AD development.Author summaryAmyloid-βis a small peptide that is widely recognized as one of the main culprits involved in the development of Alzheimer’s disease. It was recently shown that in the major subset of neurons in entorhinal cortex layer II, which expresses high levels of the protein reelin, amyloid-βand reelin bind to each other. These neurons, which are strongly involved in memory formation, are among the first to die in subjects with Alzheimer’s disease. If intracellular amyloid-β, which is clearly involved in the onset of the disease, becomes physiologically inert when it binds to reelin, it implies that reelin can prevent the neuron from being exposed to the detrimental effects of increased levels of amyloid-β. Considering that reelin expression is extraordinarily high in ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII constitute the predominant cortical site for initiation of Alzheimer’s disease. Here, we show that this paradox may be resolved if ECLII neurons have a much higher maximum amyloid-βproduction capacity than neurons expressing low levels of reelin. We provide reasons why this difference has evolved and argue that it, in a senescent physiology, predisposes ECLII neurons to initiate the development of Alzheimer’s disease.