Abstract
Apolipoprotein E (apoE) receptors act as signaling molecules in neurons, altering phosphorylation of numerous proteins after extracellular ligand binding and affecting neurite outgrowth, synapse formation, and neuronal migration. Since apoE is important in the pathogenesis of Alzheimer's disease (AD), we tested whether apoE treatment of neurons affected molecules important to phosphorylation of tau, such as GSK 3β, P35, and CDK5, and the phosphorylation of tau itself. Treatment of primary neurons with 2 uM apoE (or an apoE-derived peptide) decreased levels of phospho-GSK 3β, P35 and CDK5, and decreased levels of phosphorylated forms of tau. A lower concentration of apoE (100 nM) had no effect on these molecules. The alteration of tau phosphorylation by apoE was blocked by an inhibitor of the low-density lipoprotein receptor family, demonstrating the effects were due to receptor interactions. These results demonstrate that apoE affects several downstream signaling cascades in neurons: decreased tau kinases phosphorylation and inhibition of tau phosphorylation at Thr171 and Ser202/Thr205 epitopes. We conclude that apoE can alter levels of tau kinases and phospho-tau epitopes, potentially affecting tau neuropathological changes seen in AD brains.
Highlights
Alzheimer's disease (AD) is defined neuropathologically by the presence of two types of protein aggregates: extracellular senile plaques, which are composed of the Aβ peptide, and intraneuronal neurofibrillary tangles (NFT), which are composed of phosphorylated forms of the tau protein [1,2,3]
ApoE inhibits tau kinases in primary neurons Since Apolipoprotein E (apoE) altered activation of kinases including JNK, AKT and ERK1/2 in primary neurons [20], we tested whether apoE treatments altered activation of several kinases potentially involved with phosphorylation of tau
We have investigated how apoE signaling affects tau kinase activity and tau phosphorylation in primary neu
Summary
Alzheimer's disease (AD) is defined neuropathologically by the presence of two types of protein aggregates: extracellular senile plaques, which are composed of the Aβ peptide, and intraneuronal neurofibrillary tangles (NFT), which are composed of phosphorylated forms of the tau protein [1,2,3]. Binding of Reelin to LDL receptor family members promotes phosphorylation of the cytoplasmic disabled protein (Dab1) [16], and induces activation of Src and PKB kinases [17,18]. These processes are necessary for correct neuronal migration during development. Our results in primary neurons show that apoE treatment inhibited tau kinases (e.g., P35, P-GSK3β, and CDK5) and tau phosphorylation These data suggest that apoE could alter tau phosphorylation and potentially affect the accumulation of NFT in the AD brain
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