Abstract
Reelin is a signaling protein increasingly associated with the pathogenesis of Alzheimer’s disease that relevantly modulates tau phosphorylation. We have previously demonstrated that β-amyloid peptide (Aβ) alters reelin expression. We have now attempted to determine whether abnormal reelin triggered by Aβ will result in signaling malfunction, contributing to the pathogenic process. Here, we show that reelin forms induced by β-amyloid are less capable of down-regulating tau phosphorylation via disabled-1 and GSK3β kinase. We also demonstrate that the scaffold protein 14-3-3 that increases tau phosphorylation by modulating GSK3β activity, is up-regulated during defective reelin signaling. Binding of reelin to its receptor, mainly ApoER2 in the brain, relays the signal into the cell. We associate the impaired reelin signaling with inefficiency of reelin in forming active homodimers and decreased ability to bind efficiently to its receptor, ApoER2. More remarkably, reelin from Alzheimer cortex shows a tendency to form large complexes instead of homodimers, the active form for signaling. Our results suggest that reelin expression is altered by Aβ leading to impaired reelin signaling.
Highlights
Increasing evidence suggests that Reelin expression is altered in the Alzheimer’s disease (AD) brain
The binding of Reelin to the transmembrane liporeceptors, apolipoprotein receptor 2 (ApoER2) or the very-low-density liporeceptor (VLDLR), relays the signal into the cell via the adapter Dab1, initiating a cascade of intracytoplasmic events that ends with limited phosphorylation of the microtubule-associated tau protein, via inhibition of Glycogen synthase kinase 3 beta (GSK3β) activity; for a review, see [3]
We have previously described that treatment of SH-SY5Y neuroblastoma cells with Aβ42 influences Reelin expression and induces changes in Reelin glycosylation that resemble Reelin glycoforms observed in AD brain [11]
Summary
Increasing evidence suggests that Reelin expression is altered in the Alzheimer’s disease (AD) brain. Reelin is a signaling protein which modulates synaptic function and plasticity in the mature brain, and its signaling cascade can control tau phosphorylation [1,2]. Reduced Reelin expression has been shown to accelerate tau pathology in transgenic AD mice [6]. Ours and other studies have demonstrated an increase in Reelin levels in the AD brain and in mice overexpressing Aβ [9,10,11,12]. This could be induced by β-amyloid as Aβ treatment elevates Reelin levels [11]. The physiological consequences of alterations in Reelin expression are still unclear
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