As the population ages, neurodegenerative diseases such as Alzheimer's disease (AD) are becoming a significant burden on patients, their families, and health-care systems. Neurodegenerative processes may start up to 15 years before outward signs and symptoms of AD, as evidenced by data from AD patients and mouse models. A major genetic risk factor for late-onset AD is the e(open)4 isoform of apolipoprotein E (ApoE4), which is present in almost 20% of the population. In this review we discuss the contribution of ApoE receptor signaling to the function of each component of the tripartite synapse - the axon terminal, the postsynaptic dendritic spine, and the astrocyte - and examine how these systems fail in the context of ApoE4 and AD. Reelin signaling through apolipoprotein E (ApoE) receptors activates a signaling cascade that protects against amyloid-beta (Aβ) at the level of N-methyl-d-aspartate receptor (NMDAR) endocytosis, actin polymerization, and tau phosphorylation.ApoE4 induces neuronal resistance to Reelin by impairing the recycling of vesicles containing ApoE receptors, which results in reduced surface expression of the receptors.ApoE receptors on the presynaptic neuron affect spontaneous vesicle release by increasing the mobilization of vesicle-associated membrane protein 7 (VAMP7)-containing vesicles.Astrocytes express ApoE receptors, which may play a role in gliotransmission and synaptic pruning.
- Calcium homeostasis
- NMDA receptor
- Synaptic dysfunction
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism