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

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Trends

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.

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.

Section snippets

ApoE and the Low-Density Lipoprotein (LDL) Receptor Family

The LDL receptor family is an evolutionarily ancient and highly conserved receptor family initially identified for its role in carrying lipoprotein particles. The LDL receptor family comprises seven core members: the low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), the very-low-density lipoprotein receptor (VLDLR), megalin (LRP2), apolipoprotein E receptor 2 (Apoer2 or LRP8), LRP4, and LRP1b [1]. They share a conserved structure: a short intercellular domain containing

ApoE, ApoE Receptors, and AD

AD affects over 30 million people worldwide and one in nine people over 65 years of age [7]. AD is characterized clinically by brain shrinkage accompanied by progressive memory loss and cognitive decline as well as personality changes later in the disease course. Pathologically AD is characterized by the progressive accumulation of neuritic plaques of amyloid-beta (Aβ) followed by neurofibrillary tangles of hyperphosphorylated tau (τ). Overt clinical symptoms typically do not appear until the

Reelin, ApoE receptors, and Glutamate Signaling

Several ApoE receptors have been identified in the postsynaptic density, most notably Lrp1, Apoer2, and Vldlr, where they interact with key synaptic components. For example, Lrp1 interacts with the N-methyl-D-aspartate receptor (NMDAR) promoting endocytosis of the NMDAR from the cell surface [19]. Additionally, loss of Lrp1 hinders some elements of NMDAR signaling such as internalization of GluA1 and degradation of PSD-95 [20].

Similar to Lrp1, the ApoE receptors Apoer2/Lrp8 and Vldlr form a

Calcium Dysregulation and ApoE Receptors

One intensely discussed mechanism for how Aβ causes synaptic dysfunction early in disease is dysregulation of Ca2+ homeostasis. Ca2+ flux forms the basis of the regulation of synaptic strength: changes in Ca2+ levels in the right context trigger LTP and long-term depression (LTD), respectively. Briefly, a large Ca2+ influx through NMDARs stimulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity and G proteins, ultimately resulting in the insertion of

Postsynaptic Actin Polymerization

Maintaining Ca2+ homeostasis is essential for the regulation of postsynaptic signaling, which is important for the growth and maintenance, and alternatively the shrinkage, of dendritic spines. Dendritic spines are the central sites of postsynaptic transmission and the formation and elimination of spines is a dynamic process that continues throughout life and is dependent on many extraneuronal and intraneuronal signals [60]. Here, Reelin and ApoE receptors play a role in directing dendritic

ApoE and Endocytic Trafficking

We have so far reviewed the role of ApoE receptors and Reelin in the maintenance of synaptic plasticity and actin polymerization. As ligands for ApoE receptors, ApoE isoforms have differential effects on these processes. ApoE binds the receptors at a different site from Reelin and thus does not directly affect receptor signaling by hindering Reelin engagement; however, the ApoE isoforms do affect receptor trafficking.

ApoE exists in the human population in three isoforms, which differ at only

Presynaptic Roles of ApoE Receptors

Most work on synaptic ApoE receptors has focused on their postsynaptic roles. However, emerging data indicate that ApoE receptors have a similarly important role in regulating presynaptic vesicle release [73]. It was previously thought that LDL receptor family members were mainly expressed in the postsynaptic density; however, recent studies have shown that the ApoE receptors Apoer2 and Vldlr are also expressed at the presynaptic membrane. Briefly, Reelin signaling through Apoer2 and Vldlr on

Astrocytes

Most ApoE in the brain is expressed by astrocytes. Astrocyte-derived ApoE is important for cholesterol transport through ApoE-containing HDL-like particles, which play an important role in synaptic development and maintenance 1, 4, 5. Interestingly, recent data support the hypothesis that ApoE and the ApoE receptors mediate processes in the astrocyte outside lipid trafficking.

One role of ApoE receptor signaling in astrocytes may be modulation of synaptic pruning. Astrocytes actively partake in

Concluding Remarks and Future Perspectives

ApoE receptors have a central role as regulators of the synapse at both at pre- and postsynaptic sites as well as at the perisynaptic astrocyte. These functions, which are essential for the maintenance of proper synaptic strength, are differentially affected by ApoE isoforms, with ApoE4 most severely disrupting the neuromodulatory roles of ApoE receptors. Thus, ApoE4 promotes neuronal dysfunction at the earliest stages of the pathology, leading to the clinical manifestation of AD by two

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