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Cytosolic Phospholipase A2 Facilitates Oligomeric Amyloid-β Peptide Association with Microglia via Regulation of Membrane-Cytoskeleton Connectivity

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Abstract

Cytosolic phospholipase A2 (cPLA2) mediates oligomeric amyloid-β peptide (oAβ)-induced oxidative and inflammatory responses in glial cells. Increased activity of cPLA2 has been implicated in the neuropathology of Alzheimer’s disease (AD), suggesting that cPLA2 regulation of oAβ-induced microglial activation may play a role in the AD pathology. We demonstrate that LPS, IFNγ, and oAβ increased phosphorylated cPLA2 (p-cPLA2) in immortalized mouse microglia (BV2). Aβ association with primary rat microglia and BV2 cells, possibly via membrane-binding and/or intracellular deposition, presumably indicative of microglia-mediated clearance of the peptide, was reduced by inhibition of cPLA2. However, cPLA2 inhibition did not affect the depletion of this associated Aβ when cells were washed and incubated in a fresh medium after oAβ treatment. Since the depletion was abrogated by NH4Cl, a lysosomal inhibitor, these results suggested that cPLA2 was not involved in the degradation of the associated Aβ. To further dissect the effects of cPLA2 on microglia cell membranes, atomic force microscopy (AFM) was used to determine endocytic activity. The force for membrane tether formation (Fmtf) is a measure of membrane-cytoskeleton connectivity and represents a mechanical barrier to endocytic vesicle formation. Inhibition of cPLA2 increased Fmtf in both unstimulated BV2 cells and cells stimulated with LPS + IFNγ. Thus, increasing p-cPLA2 would decrease Fmtf, thereby increasing endocytosis. These results suggest a role of cPLA2 activation in facilitating oAβ endocytosis by microglial cells through regulation of the membrane-cytoskeleton connectivity.

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Funding

This work received financial support from the National Institute on Aging, Grant 5 R01 AG044404 (to J.C.L).

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Authors and Affiliations

  1. Department of Bioengineering, University of Illinois at Chicago, 835 S Wolcott Ave, W100, Chicago, IL, 60612, USA

    Tao Teng, Devin M. Ridgley & James C. Lee

  2. Department of Bioengineering, University of Missouri, Columbia, MO, 65211, USA

    Li Dong

  3. Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Shivesh Ghura, Matthew K. Tobin & Mary Jo LaDu

  4. Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA

    Grace Y. Sun

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  1. Tao Teng
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Teng, T., Dong, L., Ridgley, D.M. et al. Cytosolic Phospholipase A2 Facilitates Oligomeric Amyloid-β Peptide Association with Microglia via Regulation of Membrane-Cytoskeleton Connectivity. Mol Neurobiol 56, 3222–3234 (2019). https://doi.org/10.1007/s12035-018-1304-5

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