Regulatory Role of ApoE and Apoer2 in Synaptic Activity: A New Insight into Alzheimer's Disease




Chen, Ying

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Apolipoprotein E (ApoE) genotype is the major genetic modifier of late-onset Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly. By unknown mechanisms, ApoE4 isoform is strongly associated with a substantially earlier age of onset of AD. A synaptic ApoE receptor, Apoer2, activates Dab1 and Src family tyrosine kinases (SFKs) upon binding to the extracellular ligand Reelin. Here, we show that this Reelin-Apoer2-Dab1-SFKs signaling complex greatly enhances the tyrosine phosphorylation as well as the calcium conductance of NMDA receptor, a calcium-permeable postsynaptic glutamate receptor that is critical for synaptic plasticity. The simultaneous interaction of Apoer2 with both Dab1 and postsynaptic scaffolding protein PSD-95 is required for Apoer2 to activate NMDA receptor in response to Reelin. Through this NMDAR-dependent mechanism, Reelin also stimulates the phosphorylation of CREB, a transcription factor that is necessary for neuronal survival and synaptic plasticity. In addition, Reelin can potently counteract the surpression of surface NMDA receptor expression induced by Abeta peptide, the accepted causative factor in the pathogenic process of AD. These results indicate that Apoer2-mediated signaling, by counteracting depressive effect on synapses, is critical for proper function of synaptic network. Last, we show that ApoE4 impairs the trafficking and reduces the surface expression of Apoer2. Consequently, ApoE4 critically diminishes the ability of Reelin to enhance NMDA receptor activity or CREB phosphorylation in primary neurons. As a result, the ability of Reelin to enhance long-term potentiation (LTP), a form of synaptic plasticity involved in learning and memory formation, is significantly impaired in the hippocampus of mice expressing the human ApoE4 isoform. Taken together, in this thesis, we identified a novel synaptic function of Apoer2, which is to enhance NMDA receptor activity, and thereby to enhance synaptic plasticity and maintain the integrity of synaptic network. ApoE4 impairs the function of synapses by suppressing the synaptic function of Apoer2. These findings suggest a novel rational mechanism by which ApoE4 may accelerate the destabilization of synaptic network, neuronal degeneration, and eventually the progression of AD.

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