Trends in Endocrinology & Metabolism
ReviewApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
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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2023, Trends in Endocrinology and MetabolismFrom degenerative disease to malignant tumors: Insight to the function of ApoE
2023, Biomedicine and PharmacotherapyCitation Excerpt :A significant elevation of neurogranin in CSF of the ApoE4 carriers with mild cognitive impairment, which reflects synaptic damage in early cognitive impairment [75,94], and both presynaptic and postsynaptic proteins are downregulated in the brain of ApoE4-carrier mice [95]. ApoEr2 plays an important role in maintaining the structure and function of synapses and dendritic spines through the cytoplasmic adaptor proteins X11α and PSD-95 [89–93]. APOE4 inhibits the expression of ApoEr-2 on the surface of neurons and stalls the recycling of the Reelin receptors and the glutamate receptors trapped in the vesicle back to the synapse, Reelin signaling and glutamate receptor homeostasis are impaired [96].
The cell biology of APOE in the brain
2023, Trends in Cell BiologyA microcarrier-based protocol for scalable generation and purification of human induced pluripotent stem cell-derived neurons and astrocytes
2022, STAR ProtocolsCitation Excerpt :This section describes the characterization of MACS-purified astrocytes for their ability to secrete robust amounts of APOE. APOE is a lipoprotein transporter that plays critical roles related to cholesterol transport, neuronal growth, synaptic plasticity, and cell membrane repair (Lane-Donovan and Herz, 2017; Suri et al., 2013). In the central nervous system, APOE is primarily generated and secreted by functionally mature astrocytes.