ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease

Abstract

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 ɛ4 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.

Keywords: LRP; NMDA receptor; Reelin.; calcium homeostasis; dendrite; endosome; synaptic dysfunction.

Figure 1. The tripartite synapse and ApoE receptor signaling

The classic model of a synapse – with the axon terminal of one neuron synapsing onto the dendritic spine of another neuron – has been expanded to include support and signaling from the perisynaptic astrocyte, which has cell processes in close proximity with the synaptic cleft. ApoE receptor signaling affects all three components of the synapse. Panel A, electron microscopy image of a mouse hippocampal synapse courtesy of Bret Evers. Panel B, schematic rendition of the synapse in A. Numbers indicate parts of the synapse shown in greater detail in Figures 2–5.

Figure 2. ApoE receptors, Reelin, and Aβ at the post-synaptic neuron

Reelin binding to Apoer2 and Vldlr clusters the receptors and initiates a downstream signaling cascade via Dab1 that counteracts Aβ signaling at several sites, including NMDAR phosphorylation and endocytosis, tau phosphorylation, and cofilin-mediated actin depolymerization and spine remodeling.

Figure 3. ApoE4 impairs endocytic vesicle recycling

ApoE receptors are constitutively recycled to and from the surface. ApoE4 is predisposed to form molten globules as the pH drops in the early endosome, which leads to impaired vesicle recycling and reduction of surface levels of ApoE receptors and glutamate receptors.

Figure 4. Reelin signaling modulates spontaneous synaptic vesicle release

Reelin signaling through Apoer2/Vldlr on the pre-synaptic neuron stimulates influx of Ca²⁺, which specifically increases spontaneous release of VAMP7-containing vesicles.

Figure 5. ApoE receptor signaling at the astrocyte

Agrin stimulates Lrp4/MuSK complexes on astrocytes to induce release of ATP. In the extracellular space, ATP is metabolized to adenosine, which then acts on pre-synaptic A1 receptors to decrease glutamatergic vesicle release. Lrp1 on astrocytes mediates phagocytic uptake of particles, potentially including synaptosomes. ApoE isoforms differentially affect synaptosome uptake.