Decreased generation of C-terminal fragments of ApoER2 and increased reelin expression in Alzheimer’s disease

What is it about?

Reelin is a protein that is involved in synaptic function and memory signaling, and both mechanisms have been found deteriorated in Alzheimer's disease (AD). Our previous studies indicated that the β-amyloid protein (Aβ), a key protein in the AD pathology, impairs reelin activity and also increases reelin expression. In the current study, we describe that reelin protein and mRNA levels are increased in the AD brain, particularly at advanced stages, compared to control subjects. In those AD subjects that carry the expression of ApoE4 (apolipoprotein E4; i.e.: a risk factor to develop the disease), the increment in reelin mRNA levels sn lower than those ApoE4 non-carriers subjects. Reelin transmits its signals intracellularly by binding to a receptor in the cell membrane, ApoER2 (apolipoprotein E receptor 2). When reelin binds to ApoER2, the receptor is processed, generating intracellular fragments which are able to modulate reelin expression. We found that the levels of these ApoER2 fragments appeared significantly lower in cultured cells treated with Aβ and in brain extracts from advanced AD. Our data suggest that Aβ interferes in reelin signaling, precluding the generation of ApoER2 fragments and therefore, interfering in reelin expression, likely contributing to the progression of AD.

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