Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10186-91. Epub 2016 Aug 24 PubMed.

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  1. This work is highly exciting. It introduces a new dimension to the diverse functions of ApoE as a risk factor for AD. Although the primary function of ApoE expressed in astrocytes is to transport lipids such as cholesterol, additional roles in neuronal signaling, vascular homeostasis, and inflammatory responses have been proposed, and it seems to regulate both the clearance and aggregation of amyloid-beta peptides in the pathogenesis of AD. Thus, the newly defined function of ApoE in regulating the phagocytic function of astrocytes in an isoform-dependent manner suggests that an even more complex network of functions might collectively contribute to the increased risk for AD conferred by APOE4.

    Another interesting dimension of this work is the emphasis of a phagocytic function of astrocytes, which is better known for microglia, the resident innate immune cells in the brain that also express ApoE. The data supporting a role for ApoE in modulating phagocytic efficiency appears to be solid; however, the underlying mechanism is not clear. ApoE binds to a variety of cell surface receptors, including transport receptors LRP1 and LDLR, as well as signaling receptors ApoER2/LRP8 and VLDLR. Whether one or more of these ApoE receptors or an alternative receptor mediates the ApoE isoform-dependent effects on phagocytosis requires further study. Further, the in vivo relevance of this work requires investigation using model systems exhibiting AD-related pathologies. The human relevance is even more difficulty to define but perhaps can be addressed by analyzing pathways relevant to the phagocytic function of astrocytes in human AD brains with different APOE genotypes. Overall, this is a highly interesting finding that warrants follow-up studies on both mechanisms and relevance.

    View all comments by Guojun Bu

  2. This is an intriguing publication that continues the authors’ premise that astrocytes play an active role in synaptic phagocytosis. In 2013, Chung and collaborators proposed a new role for astrocytes in the adult brain, specifically phagocytosis activated not via the compliment cascade but through the MEGF10 and MERTK pathways (Chung et al., 2013). Stevens and co-workers demonstrated that factors secreted by activated astrocytes induce C1q secretion by neurons and microglia, initiating the complement cascade in microglia, leading to phagocytosis of synapses (Stevens et al., 2007; Stephan et al., 2012). C1q is of particular interest as it is upregulated during aging and neurodegeneration (Stephan et al., 2013) and has recently been demonstrated to mediate the early synapse loss in AD mouse models (Hong et al., 2016). This present study by Chung and collaborators incorporates the role of APOE genotype in these novel astrocytic pathways. The authors analyzed primary astrocytes from APOE-KI mice and developing brains to demonstrate that APOE modulates the capacity of astrocytes to engulf synaptosomes, in the order APOE2>APOE3>APOE4. In addition, age-induced C1q accumulation is reduced with APOE2 and increased with APOE4. These data provide a new mechanism for the APOE4-related neurodegeneration and APOE2-related neuroprotection, namely phagocytic capacity.

    As the authors point out, future studies are required to elucidate how APOE genotype regulates astrocytic phagocytosis, including interactions with the MEGF10, MERTK, and even complement pathways, and how this regulation is affected by APOE genotype, aging, and neurodegeneration. The interaction with C1q is also important but apparently contradictory as an increase in C1q has been reported to promote neuronal survival (Heese  et al., 1998; Pisalyaput and Tenner, 2008; Benoit  and Tenner, 2011), while C1q-knock out leads to a decrease in phagocytic microglia and early synapse loss (Stephan et al., 2012; Hong et al., 2016). Critical to these questions are the interactions between astrocytes and microglia. As well, in a long-term (28 days) neuron/glial co-culture model, apoE4 delays spine formation and accelerates the loss of mature spines, while apoE2 enhances both spine formation and maintenance (Nwabuisi-Heath et al., 2013). 

    To incorporate these findings with APOE associated AD risk, it is necessary to evaluate these pathways in an AD/APOE relevant model. Unpublished RNA-Seq data in our EFAD mice (human APOE expressed in 5XFAD mice), demonstrate that complement cascade pathways were significant in E3FAD vs E4FAD (three of the top four pathways with Metacore analysis), supporting the importance of these mechanisms in AD pathology. 

    References:

    Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A, Chakraborty C, Joung J, Foo LC, Thompson A, Chen C, Smith SJ, Barres BA. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013 Dec 19;504(7480):394-400. Epub 2013 Nov 24 PubMed.

    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA. The classical complement cascade mediates CNS synapse elimination. Cell. 2007 Dec 14;131(6):1164-78. PubMed.

    Stephan AH, Barres BA, Stevens B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369-89. PubMed.

    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA, Coutellier L, Kim L, Tsai HH, Huang EJ, Rowitch DH, Berns DS, Tenner AJ, Shamloo M, Barres BA. A Dramatic Increase of C1q Protein in the CNS during Normal Aging. J Neurosci. 2013 Aug 14;33(33):13460-74. PubMed.

    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.

    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. Epub 2016 Mar 31 PubMed.

    Pisalyaput K, Tenner AJ. Complement component C1q inhibits beta-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanisms. J Neurochem. 2008 Feb;104(3):696-707. PubMed.

    Benoit ME, Tenner AJ. Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression. J Neurosci. 2011 Mar 2;31(9):3459-69. PubMed.

    Nwabuisi-Heath E, Rebeck GW, Ladu MJ, Yu C. ApoE4 delays dendritic spine formation during neuron development and accelerates loss of mature spines in vitro. ASN Neuro. 2014 Jan 13;6(1):e00134. PubMed.

    View all comments by María Evangelina Avila-Munoz

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  1. ApoE Variants Modulate Astrocyte Appetite for Synapses

Mutations

  1. APOE R176C (ApoE2)