Skip to main content

Advertisement

SpringerLink
Log in

Phosphatidylserine in the Nervous System: Cytoplasmic Regulator of the AKT and PKC Signaling Pathways and Extracellular “Eat-Me” Signal in Microglial Phagocytosis

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Phosphatidylserine (PtdSer) is an important anionic phospholipid found in eukaryotic cells and has been proven to serve as a beneficial factor in the treatment of neurodegenerative diseases. PtdSer resides in the inner leaflet of the plasma membrane, where it is involved in regulating the AKT and PKC signaling pathways; however, it becomes exposed to the extracellular leaflet during neurodevelopmental processes and neurodegenerative diseases, participating in microglia-mediated synaptic and neuronal phagocytosis. In this paper, we review several characteristics of PtdSer, including the synthesis and translocation of PtdSer, the functions of cytoplasmic and exposed PtdSer, and different PtdSer-detection materials used to further understand the role of PtdSer in the nervous system.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

Not applicable.

Abbreviations

AD:

Alzheimer’s disease

AKT:

Protein kinase B

AnxA5:

Annexin A5

BAI1:

Brain-specific angiogenesis inhibitor 1

BDNF:

Brain-derived neurotrophic factor

C1q:

Complement component 1, q subcomponent

CDC50A:

Cell division cycle protein 50A

CNS:

Central nervous system

CR3:

Complement receptor 3

DHA:

Docosahexaenoic acid

GABA:

Gamma-aminobutyric acid

Caspase:

Cysteine-containing aspartate-specific proteases

GAS6:

Growth arrest-specific 6

GPR56:

Adhesion G protein-coupled receptor G1

Lact-C2:

C2 domain in Lactadherin

MFGE8:

Milk fat globule epidermal growth factor 8

NBD:

Nitrobenzoxadiazole

NBD-PS:

Nitrobenzoxadiazole-labeled Ptdser

P4-ATPase:

Type IV P-type adenosine triphosphatase

PET:

Positron emission tomography

PH domain:

Pleckstrin homology domain

PIP3 :

Phosphatidylinositol (3,4,5)-trisphosphate

PKC:

Protein kinase C

PtdCho:

Phosphatidylcholine

PtdEtn:

Phosphatidylethanolamine

PtdSer:

Phosphatidylserine

pSIVA:

Polarity-sensitive annexin-based biosensor

PSS:

Phosphatidylserine synthase

RAGE:

Receptor for advanced glycation end products

ROS:

Reactive oxygen species

RTKs:

Receptor protein tyrosine kinase

SAMP8:

Senescence-accelerated mouse-prone 8

TAM:

Receptor tyrosine kinases TYRO3, AXL, and MER

TIM:

T cell/transmembrane, immunoglobulin and mucin

TMEM16F:

Transmembrane protein 16F

TREM2:

Triggering receptor expressed on myeloid cells 2

Xkr8:

Xk-related protein 8

References

  1. Svennerholm L (1968) Distribution and fatty acid composition of phosphoglycerides in normal human brain. J Lipid Res 9(5):570–579

    Article  CAS  Google Scholar 

  2. Kimura AK, Kim HY (2013) Phosphatidylserine synthase 2: high efficiency for synthesizing phosphatidylserine containing docosahexaenoic acid. J Lipid Res 54(1):214–222

    Article  CAS  Google Scholar 

  3. Kim HY, Huang BX, Spector AA (2014) Phosphatidylserine in the brain: metabolism and function. Prog Lipid Res 56:1–18

    Article  CAS  Google Scholar 

  4. Scott-Hewitt N et al (2020) Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia. Embo j 39(16):e105380

    Article  CAS  Google Scholar 

  5. Park J et al (2021) Microglial MERTK eliminates phosphatidylserine-displaying inhibitory post-synapses. Embo j 40(15):e107121

    Article  CAS  Google Scholar 

  6. Bader Lange ML et al (2008) Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease. Neurobiol Dis 29(3):456–464

    Article  CAS  Google Scholar 

  7. Brelstaff J et al (2018) Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep 24(8):1939-1948.e4

    Article  CAS  Google Scholar 

  8. Brelstaff JH et al (2021) Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates. Sci Adv 7(43):eabg4980

    Article  CAS  Google Scholar 

  9. Pampuscenko K et al (2020) Extracellular tau induces microglial phagocytosis of living neurons in cell cultures. J Neurochem 154(3):316–329

    Article  CAS  Google Scholar 

  10. Huang Y et al (2021) Microglia use TAM receptors to detect and engulf amyloid β plaques. Nat Immunol 22(5):586–594

    Article  CAS  Google Scholar 

  11. Vance JE (2008) Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids. J Lipid Res 49(7):1377–1387

    Article  CAS  Google Scholar 

  12. Arikketh D, Nelson R, Vance JE (2008) Defining the importance of phosphatidylserine synthase-1 (PSS1): unexpected viability of PSS1-deficient mice. J Biol Chem 283(19):12888–12897

    Article  CAS  Google Scholar 

  13. Pettegrew JW et al (2001) Brain membrane phospholipid alterations in Alzheimer’s disease. Neurochem Res 26(7):771–782

    Article  CAS  Google Scholar 

  14. Kim BK, Park SK (2020) Phosphatidylserine modulates response to oxidative stress through hormesis and increases lifespan via DAF-16 in Caenorhabditis elegans. Biogerontology 21(2):231–244

    Article  CAS  Google Scholar 

  15. Akyol S et al (2021) Lipid profiling of Alzheimer’s disease brain highlights enrichment in glycerol(phospho)lipid, and sphingolipid metabolism. Cells 10(10):2591

    Article  CAS  Google Scholar 

  16. Zhang W et al (2015) n-3 Polyunsaturated fatty acids reduce neonatal hypoxic/ischemic brain injury by promoting phosphatidylserine formation and Akt signaling. Stroke 46(10):2943–2950

    Article  CAS  Google Scholar 

  17. Kingsley M (2006) Effects of phosphatidylserine supplementation on exercising humans. Sports Med 36(8):657–669

    Article  Google Scholar 

  18. More MI, Freitas U, Rutenberg D (2014) Positive effects of soy lecithin-derived phosphatidylserine plus phosphatidic acid on memory, cognition, daily functioning, and mood in elderly patients with Alzheimer’s disease and dementia. Adv Ther 31(12):1247–1262

    Article  CAS  Google Scholar 

  19. Chaung HC et al (2013) Docosahexaenoic acid and phosphatidylserine improves the antioxidant activities in vitro and in vivo and cognitive functions of the developing brain. Food Chem 138(1):342–347

    Article  CAS  Google Scholar 

  20. Nishizuka Y (1984) Turnover of inositol phospholipids and signal transduction. Science 225(4668):1365–1370

    Article  CAS  Google Scholar 

  21. Suzuki S et al (2001) Oral administration of soybean lecithin transphosphatidylated phosphatidylserine improves memory impairment in aged rats. J Nutr 131(11):2951–2956

    Article  CAS  Google Scholar 

  22. Kay JG, Fairn GD (2019) Distribution, dynamics and functional roles of phosphatidylserine within the cell. Cell Commun Signal 17(1):126

    Article  Google Scholar 

  23. Park YJ et al (2021) Phosphatidylserine synthase plays an essential role in glia and affects development, as well as the maintenance of neuronal function. iScience 24(8):102899

    Article  CAS  Google Scholar 

  24. von Schacky C (2021) Importance of EPA and DHA blood levels in brain structure and function. Nutrients 13(4):1074

    Article  Google Scholar 

  25. Lauritzen L et al (2016) DHA effects in brain development and function. Nutrients 8(1):6

    Article  Google Scholar 

  26. Kim HY, Akbar M, Kim YS (2010) Phosphatidylserine-dependent neuroprotective signaling promoted by docosahexaenoic acid. Prostaglandins Leukot Essent Fatty Acids 82(4–6):165–172

    Article  CAS  Google Scholar 

  27. Guo M et al (2007) Neuronal specific increase of phosphatidylserine by docosahexaenoic acid. J Mol Neurosci 33(1):67–73

    Article  CAS  Google Scholar 

  28. Wu A, Ying Z, Gomez-Pinilla F (2008) Docosahexaenoic acid dietary supplementation enhances the effects of exercise on synaptic plasticity and cognition. Neuroscience 155(3):751–759

    Article  CAS  Google Scholar 

  29. Wurtman RJ (2008) Synapse formation and cognitive brain development: effect of docosahexaenoic acid and other dietary constituents. Metabolism 57(Suppl 2):S6-10

    Article  CAS  Google Scholar 

  30. Benfenati F et al (1989) Electrostatic and hydrophobic interactions of synapsin I and synapsin I fragments with phospholipid bilayers. J Cell Biol 108(5):1851–1862

    Article  CAS  Google Scholar 

  31. Cheetham JJ et al (2001) Identification of synapsin I peptides that insert into lipid membranes. Biochem J 354(Pt 1):57–66

    Article  CAS  Google Scholar 

  32. Zhou MM et al (2018) Mechanisms of DHA-enriched phospholipids in improving cognitive deficits in aged SAMP8 mice with high-fat diet. J Nutr Biochem 59:64–75

    Article  CAS  Google Scholar 

  33. Xu ZJ et al (2021) A comparative study of the effects of phosphatidylserine rich in DHA and EPA on Aβ-induced Alzheimer’s disease using cell models. Food Funct 12(10):4411–4423

    Article  CAS  Google Scholar 

  34. He Y et al (2021) Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 6(1):425

    Article  CAS  Google Scholar 

  35. Alkon DL, Sun MK, Nelson TJ (2007) PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer’s disease. Trends Pharmacol Sci 28(2):51–60

    Article  CAS  Google Scholar 

  36. Vasudevan KM, Garraway LA (2010) AKT signaling in physiology and disease. Curr Top Microbiol Immunol 347:105–133

    CAS  Google Scholar 

  37. Huang BX et al (2011) Phosphatidylserine is a critical modulator for Akt activation. J Cell Biol 192(6):979–992

    Article  CAS  Google Scholar 

  38. Zhang Z et al (2018) PI3K/Akt and HIF1 signaling pathway in hypoxiaischemia (Review). Mol Med Rep 18(4):3547–3554

    CAS  Google Scholar 

  39. Rai SN et al (2019) The role of PI3K/Akt and ERK in neurodegenerative disorders. Neurotox Res 35(3):775–795

    Article  CAS  Google Scholar 

  40. Duggan MR, Weaver M, Khalili K (2021) PAM (PIK3/AKT/mTOR) signaling in glia: potential contributions to brain tumors in aging. Aging (Albany NY) 13(1):1510–1527

    Article  CAS  Google Scholar 

  41. Gabbouj S et al (2019) Altered insulin signaling in Alzheimer’s disease brain—special emphasis on PI3K-Akt pathway. Front Neurosci 13:629

    Article  Google Scholar 

  42. Mellor H, Parker PJ (1998) The extended protein kinase C superfamily. Biochem J 332(Pt 2):281–292

    Article  CAS  Google Scholar 

  43. Geribaldi-Doldan N et al (2019) Protein kinase C: targets to regenerate brain injuries? Front Cell Dev Biol 7:39

    Article  Google Scholar 

  44. Newton AC (2010) Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab 298(3):E395-402

    Article  CAS  Google Scholar 

  45. Verdaguer N et al (1999) Ca(2+) bridges the C2 membrane-binding domain of protein kinase Calpha directly to phosphatidylserine. Embo j 18(22):6329–6338

    Article  CAS  Google Scholar 

  46. Saito N, Shirai Y (2002) Protein kinase C gamma (PKC gamma): function of neuron specific isotype. J Biochem 132(5):683–687

    Article  CAS  Google Scholar 

  47. Chopra R et al (2018) Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia. Hum Mol Genet 27(8):1396–1410

    Article  CAS  Google Scholar 

  48. Schumacher D et al (2021) Phosphatidylserine supplementation as a novel strategy for reducing myocardial infarct size and preventing adverse left ventricular remodeling. Int J Mol Sci 22(9):4401

    Article  CAS  Google Scholar 

  49. Kim PM, Kornberg MD (2022) Targeting PKC in microglia to promote remyelination and repair in the CNS. Curr Opin Pharmacol 62:103–108

    Article  CAS  Google Scholar 

  50. Hornik TC, Neniskyte U, Brown GC (2014) inflammation induces multinucleation of microglia via PKC inhibition of cytokinesis, generating highly phagocytic multinucleated giant cells. J Neurochem 128(5):650–661

    Article  CAS  Google Scholar 

  51. Poon IK et al (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14(3):166–180

    Article  CAS  Google Scholar 

  52. Nagata S, Sakuragi T, Segawa K (2020) Flippase and scramblase for phosphatidylserine exposure. Curr Opin Immunol 62:31–38

    Article  CAS  Google Scholar 

  53. Shin HW, Takatsu H (2020) Phosphatidylserine exposure in living cells. Crit Rev Biochem Mol Biol 55(2):166–178

    Article  CAS  Google Scholar 

  54. Palmgren MG, Nissen P (2011) P-type ATPases. Annu Rev Biophys 40:243–266

    Article  CAS  Google Scholar 

  55. Andersen JP et al (2016) P4-ATPases as phospholipid flippases-structure, function, and enigmas. Front Physiol 7:275

    Article  Google Scholar 

  56. Coleman JA, Molday RS (2011) Critical role of the beta-subunit CDC50A in the stable expression, assembly, subcellular localization, and lipid transport activity of the P4-ATPase ATP8A2. J Biol Chem 286(19):17205–17216

    Article  CAS  Google Scholar 

  57. Segawa K, Kurata S, Nagata S (2018) The CDC50A extracellular domain is required for forming a functional complex with and chaperoning phospholipid flippases to the plasma membrane. J Biol Chem 293(6):2172–2182

    Article  CAS  Google Scholar 

  58. Timcenko M et al (2019) Structure and autoregulation of a P4-ATPase lipid flippase. Nature 571(7765):366–370

    Article  CAS  Google Scholar 

  59. Timcenko M et al (2021) Structural basis of substrate-independent phosphorylation in a P4-ATPase lipid flippase. J Mol Biol 433(16):167062

    Article  CAS  Google Scholar 

  60. Shin HW, Takatsu H (2019) Substrates of P4-ATPases: beyond aminophospholipids (phosphatidylserine and phosphatidylethanolamine). Faseb j 33(3):3087–3096

    Article  CAS  Google Scholar 

  61. Wang J et al (2018) Proteomic analysis and functional characterization of P4-ATPase phospholipid flippases from murine tissues. Sci Rep 8(1):10795

    Article  Google Scholar 

  62. Segawa K et al (2014) Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344(6188):1164–1168

    Article  CAS  Google Scholar 

  63. Segawa K et al. (2021) A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes. J Clin Invest 131(18):e148005. https://doi.org/10.1172/JCI148005

  64. Nakanishi H et al (2020) Transport cycle of plasma membrane flippase ATP11C by Cryo-EM. Cell Rep 32(13):108208

    Article  CAS  Google Scholar 

  65. Takatsu H et al (2011) ATP9B, a P4-ATPase (a putative aminophospholipid translocase), localizes to the trans-Golgi network in a CDC50 protein-independent manner. J Biol Chem 286(44):38159–38167

    Article  CAS  Google Scholar 

  66. Levano K et al (2012) Atp8a1 deficiency is associated with phosphatidylserine externalization in hippocampus and delayed hippocampus-dependent learning. J Neurochem 120(2):302–313

    Article  CAS  Google Scholar 

  67. Wang J et al (2019) ATP11B deficiency leads to impairment of hippocampal synaptic plasticity. J Mol Cell Biol 11(8):688–702

    Article  CAS  Google Scholar 

  68. Xu Q et al (2012) P4-ATPase ATP8A2 acts in synergy with CDC50A to enhance neurite outgrowth. FEBS Lett 586(13):1803–1812

    Article  CAS  Google Scholar 

  69. Sann S et al (2009) Roles of endosomal trafficking in neurite outgrowth and guidance. Trends Cell Biol 19(7):317–324

    Article  CAS  Google Scholar 

  70. Pedemonte N, Galietta LJ (2014) Structure and function of TMEM16 proteins (anoctamins). Physiol Rev 94(2):419–459

    Article  CAS  Google Scholar 

  71. Suzuki J et al (2013) Calcium-dependent phospholipid scramblase activity of TMEM16 protein family members. J Biol Chem 288(19):13305–13316

    Article  CAS  Google Scholar 

  72. Fujii T et al (2015) TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets. Proc Natl Acad Sci U S A 112(41):12800–12805

    Article  CAS  Google Scholar 

  73. Zhang Y et al (2020) TMEM16F aggravates neuronal loss by mediating microglial phagocytosis of neurons in a rat experimental cerebral ischemia and reperfusion model. Front Immunol 11:1144

    Article  CAS  Google Scholar 

  74. Suzuki J et al (2013) Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341(6144):403–406

    Article  CAS  Google Scholar 

  75. Suzuki J, Imanishi E, Nagata S (2016) Xkr8 phospholipid scrambling complex in apoptotic phosphatidylserine exposure. Proc Natl Acad Sci U S A 113(34):9509–9514

    Article  CAS  Google Scholar 

  76. Sakuragi T, Kosako H, Nagata S (2019) Phosphorylation-mediated activation of mouse Xkr8 scramblase for phosphatidylserine exposure. Proc Natl Acad Sci U S A 116(8):2907–2912

    Article  CAS  Google Scholar 

  77. Kautzman AG et al (2018) Xkr8 modulates bipolar cell number in the mouse retina. Front Neurosci 12:876

    Article  Google Scholar 

  78. Segawa K, Nagata S (2015) An Apoptotic “Eat Me” signal: phosphatidylserine exposure. Trends Cell Biol 25(11):639–650

    Article  CAS  Google Scholar 

  79. Lemke G (2019) How macrophages deal with death. Nat Rev Immunol 19(9):539–549

    Article  CAS  Google Scholar 

  80. Païdassi H et al (2008) C1q binds phosphatidylserine and likely acts as a multiligand-bridging molecule in apoptotic cell recognition. J Immunol 180(4):2329–2338

    Article  Google Scholar 

  81. Filipello F et al (2018) The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity. Immunity 48(5):979-991e8

    Article  CAS  Google Scholar 

  82. Li T et al (2020) A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding. Embo j 39(16):e104136

    Article  CAS  Google Scholar 

  83. O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204

    Article  CAS  Google Scholar 

  84. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318

    Article  CAS  Google Scholar 

  85. Weinhard L et al (2018) Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun 9(1):1228

    Article  Google Scholar 

  86. Basilico B et al (2019) Microglia shape presynaptic properties at developing glutamatergic synapses. Glia 67(1):53–67

    Article  Google Scholar 

  87. Filipello F et al (2018) The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity. Immunity 48(5):979-991.e8

    Article  CAS  Google Scholar 

  88. Werneburg S et al (2020) Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease. Immunity 52(1):167-182.e7

    Article  CAS  Google Scholar 

  89. Lemke G (2013) Biology of the TAM receptors. Cold Spring Harb Perspect Biol 5(11):a009076

    Article  Google Scholar 

  90. Lemke G, Rothlin CV (2008) Immunobiology of the TAM receptors. Nat Rev Immunol 8(5):327–336

    Article  CAS  Google Scholar 

  91. Lemke G (2017) Phosphatidylserine is the signal for TAM receptors and their ligands. Trends Biochem Sci 42(9):738–748

    Article  CAS  Google Scholar 

  92. Huang M et al (2003) Structural basis of membrane binding by Gla domains of vitamin K-dependent proteins. Nat Struct Biol 10(9):751–756

    Article  CAS  Google Scholar 

  93. Lew ED et al (2014) Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. Elife 3:e03385

    Article  Google Scholar 

  94. Geng K et al (2017) Requirement of gamma-carboxyglutamic acid modification and phosphatidylserine binding for the activation of Tyro3, Axl, and Mertk receptors by growth arrest-specific 6. Front Immunol 8:1521

    Article  Google Scholar 

  95. Fourgeaud L et al (2016) TAM receptors regulate multiple features of microglial physiology. Nature 532(7598):240–244

    Article  CAS  Google Scholar 

  96. Chung WS et al (2013) Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504(7480):394–400

    Article  CAS  Google Scholar 

  97. Ji R et al (2014) TAM receptors support neural stem cell survival, proliferation and neuronal differentiation. PLoS ONE 9(12):e115140

    Article  Google Scholar 

  98. Ji R et al (2015) TAM receptor deficiency affects adult hippocampal neurogenesis. Metab Brain Dis 30(3):633–644

    Article  CAS  Google Scholar 

  99. Blades F et al (2018) The TAM receptor TYRO3 is a critical regulator of myelin thickness in the central nervous system. Glia 66(10):2209–2220

    Article  Google Scholar 

  100. Tondo G, Perani D, Comi C (2019) TAM receptor pathways at the crossroads of neuroinflammation and neurodegeneration. Dis Markers 2019:2387614

    Article  Google Scholar 

  101. Shafit-Zagardo B, Gruber RC, DuBois JC (2018) The role of TAM family receptors and ligands in the nervous system: From development to pathobiology. Pharmacol Ther 188:97–117

    Article  CAS  Google Scholar 

  102. Prieto AL et al (2007) Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neurons. Neuroscience 150(2):319–334

    Article  CAS  Google Scholar 

  103. Gautier EL et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13(11):1118–1128

    Article  CAS  Google Scholar 

  104. Wu H et al (2021) Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury. J Neuroinflammation 18(1):2

    Article  CAS  Google Scholar 

  105. Condello C et al (2015) Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat Commun 6:6176

    Article  CAS  Google Scholar 

  106. Owlett LD et al (2022) Gas6 induces inflammation and reduces plaque burden but worsens behavior in a sex-dependent manner in the APP/PS1 model of Alzheimer’s disease. J Neuroinflammation 19(1):38

    Article  CAS  Google Scholar 

  107. Freeman GJ et al (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235(1):172–189

    Article  CAS  Google Scholar 

  108. De Maeyer RPH et al (2020) Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat Immunol 21(6):615–625

    Article  Google Scholar 

  109. Liu W et al (2019) Tim-4 Inhibits NLRP3 Inflammasome via the LKB1/AMPKα Pathway in Macrophages. J Immunol 203(4):990–1000

    Article  CAS  Google Scholar 

  110. Tan S et al (2020) Tim-3 hampers tumor surveillance of liver-resident and conventional NK cells by disrupting PI3K signaling. Cancer Res 80(5):1130–1142

    Article  CAS  Google Scholar 

  111. Min C et al (2020) Tim-4 functions as a scavenger receptor for phagocytosis of exogenous particles. Cell Death Dis 11(7):561

    Article  CAS  Google Scholar 

  112. Wang HW et al (2015) Microglia activity modulated by T cell Ig and mucin domain protein 3 (Tim-3). Cell Immunol 293(1):49–58

    Article  CAS  Google Scholar 

  113. Koh HS et al (2015) The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia. Nat Commun 6:6340

    Article  CAS  Google Scholar 

  114. Mazaheri F et al (2014) Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia. Nat Commun 5:4046

    Article  CAS  Google Scholar 

  115. Park D, Ravichandran KS (2010) Emerging roles of brain-specific angiogenesis inhibitor 1. Adv Exp Med Biol 706:167–178

    Article  CAS  Google Scholar 

  116. Park D et al (2007) BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450(7168):430–434

    Article  CAS  Google Scholar 

  117. Tu YK, Duman JG, Tolias KF (2018) The adhesion-GPCR BAI1 promotes excitatory synaptogenesis by coordinating bidirectional trans-synaptic signaling. J Neurosci 38(39):8388–8406

    Article  CAS  Google Scholar 

  118. Sokolowski JD et al (2011) Brain-specific angiogenesis inhibitor-1 expression in astrocytes and neurons: implications for its dual function as an apoptotic engulfment receptor. Brain Behav Immun 25(5):915–921

    Article  CAS  Google Scholar 

  119. Duman JG, Tu YK, Tolias KF (2016) Emerging roles of BAI adhesion-GPCRs in synapse development and plasticity. Neural Plast 2016:8301737

    Article  Google Scholar 

  120. Zhu D et al (2015) BAI1 regulates spatial learning and synaptic plasticity in the hippocampus. J Clin Invest 125(4):1497–1508

    Article  Google Scholar 

  121. Duman JG et al (2013) The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites. J Neurosci 33(16):6964–6978

    Article  CAS  Google Scholar 

  122. Nishi C et al (2014) Tim4- and MerTK-mediated engulfment of apoptotic cells by mouse resident peritoneal macrophages. Mol Cell Biol 34(8):1512–1520

    Article  Google Scholar 

  123. Yanagihashi Y et al (2017) Mouse macrophages show different requirements for phosphatidylserine receptor Tim4 in efferocytosis. Proc Natl Acad Sci U S A 114(33):8800–8805

    Article  CAS  Google Scholar 

  124. Park D, Hochreiter-Hufford A, Ravichandran KS (2009) The phosphatidylserine receptor TIM-4 does not mediate direct signaling. Curr Biol 19(4):346–351

    Article  Google Scholar 

  125. Lee J et al (2019) A scaffold for signaling of Tim-4-mediated efferocytosis is formed by fibronectin. Cell Death Differ 26(9):1646–1655

    Article  CAS  Google Scholar 

  126. Salzman GS et al (2016) Structural basis for regulation of GPR56/ADGRG1 by its alternatively spliced extracellular domains. Neuron 91(6):1292–1304

    Article  CAS  Google Scholar 

  127. Fricker M et al (2012) MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation. J Neurosci 32(8):2657–2666

    Article  CAS  Google Scholar 

  128. Elliott MR, Ravichandran KS (2010) Clearance of apoptotic cells: implications in health and disease. J Cell Biol 189(7):1059–1070

    Article  CAS  Google Scholar 

  129. Akakura S et al (2004) The opsonin MFG-E8 is a ligand for the alphavbeta5 integrin and triggers DOCK180-dependent Rac1 activation for the phagocytosis of apoptotic cells. Exp Cell Res 292(2):403–416

    Article  CAS  Google Scholar 

  130. Cserép C et al (2020) Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science 367(6477):528–537

    Article  Google Scholar 

  131. Butler CA et al (2021) Microglial phagocytosis of neurons in neurodegeneration, and its regulation. J Neurochem 158(3):621–639

    Article  CAS  Google Scholar 

  132. Carpanini SM, Torvell M, Morgan BP (2019) Therapeutic inhibition of the complement system in diseases of the central nervous system. Front Immunol 10:362

    Article  CAS  Google Scholar 

  133. van de Bovenkamp FS et al (2021) Circulating C1q levels in health and disease, more than just a biomarker. Mol Immunol 140:206–216

    Article  Google Scholar 

  134. Dalakas MC, Alexopoulos H, Spaeth PJ (2020) Complement in neurological disorders and emerging complement-targeted therapeutics. Nat Rev Neurol 16(11):601–617

    Article  Google Scholar 

  135. Martin M, Leffler J, Blom AM (2012) Annexin A2 and A5 serve as new ligands for C1q on apoptotic cells. J Biol Chem 287(40):33733–33744

    Article  CAS  Google Scholar 

  136. Wang S. et al. (2020) Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med 217(9):e20200785. https://doi.org/10.1084/jem.20200785

  137. Ulland TK et al (2017) TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170(4):649-663.e13

    Article  CAS  Google Scholar 

  138. Wang Y et al (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160(6):1061–1071

    Article  CAS  Google Scholar 

  139. Konishi H, Kiyama H (2018) Microglial TREM2/DAP12 signaling: a double-edged sword in neural diseases. Front Cell Neurosci 12:206

    Article  Google Scholar 

  140. Cosker K et al (2021) Microglial signalling pathway deficits associated with the patient derived R47H TREM2 variants linked to AD indicate inability to activate inflammasome. Sci Rep 11(1):13316

    Article  CAS  Google Scholar 

  141. Akkermann R et al (2017) The TAM receptor Tyro3 regulates myelination in the central nervous system. Glia 65(4):581–591

    Article  Google Scholar 

  142. Lemke G, Burstyn-Cohen T (2010) TAM receptors and the clearance of apoptotic cells. Ann N Y Acad Sci 1209:23–29

    Article  CAS  Google Scholar 

  143. Schwanzel-Fukuda M, Pfaff DW (1989) Origin of luteinizing hormone-releasing hormone neurons. Nature 338(6211):161–164

    Article  CAS  Google Scholar 

  144. Allen MP et al (2002) Adhesion-related kinase repression of gonadotropin-releasing hormone gene expression requires Rac activation of the extracellular signal-regulated kinase pathway. J Biol Chem 277(41):38133–38140

    Article  CAS  Google Scholar 

  145. Bellan M, Pirisi M, Sainaghi PP (2016) The Gas6/TAM System and Multiple Sclerosis. Int J Mol Sci 17(11):1807

    Article  Google Scholar 

  146. Weinger JG et al (2011) Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis. J Neuroinflammation 8:49

    Article  Google Scholar 

  147. Binder MD et al (2016) Common and low frequency variants in MERTK are independently associated with multiple sclerosis susceptibility with discordant association dependent upon HLA-DRB1*15:01 Status. PLoS Genet 12(3):e1005853

    Article  Google Scholar 

  148. Zheng L et al (2020) Inhibition of TIM-4 protects against cerebral ischaemia-reperfusion injury. J Cell Mol Med 24(2):1276–1285

    Article  CAS  Google Scholar 

  149. Chen ZQ et al (2019) Negative regulation of glial Tim-3 inhibits the secretion of inflammatory factors and modulates microglia to antiinflammatory phenotype after experimental intracerebral hemorrhage in rats. CNS Neurosci Ther 25(6):674–684

    Article  CAS  Google Scholar 

  150. Kim HS et al (2020) Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment. Cancer Res 80(9):1833–1845

    Article  CAS  Google Scholar 

  151. Choi JS et al (2018) New targets for Parkinson’s disease: adhesion G protein-coupled receptor B1 is downregulated by AMP-activated protein kinase activation. Omics-a J Integr Biol 22(7):493–501

    Article  CAS  Google Scholar 

  152. Cork SM, Van Meir EG (2011) Emerging roles for the BAI1 protein family in the regulation of phagocytosis, synaptogenesis, neurovasculature, and tumor development. J Mol Med (Berl) 89(8):743–752

    Article  CAS  Google Scholar 

  153. Murayama AY et al (2020) The polymicrogyria-associated GPR56 promoter preferentially drives gene expression in developing GABAergic neurons in common marmosets. Sci Rep 10(1):21516

    Article  CAS  Google Scholar 

  154. Chiou B et al (2021) Cell type-specific evaluation of ADGRG1/GPR56 function in developmental central nervous system myelination. Glia 69(2):413–423

    Article  CAS  Google Scholar 

  155. Li QS, Sun Y, Wang T (2020) Epigenome-wide association study of Alzheimer’s disease replicates 22 differentially methylated positions and 30 differentially methylated regions. Clin Epigenetics 12(1):149

    Article  CAS  Google Scholar 

  156. Alavi MS, Karimi G, Roohbakhsh A (2019) The role of orphan G protein-coupled receptors in the pathophysiology of multiple sclerosis: A review. Life Sci 224:33–40

    Article  CAS  Google Scholar 

  157. Baek WY et al (2019) Polymorphisms of MFGE8 are associated with susceptibility and clinical manifestations through gene expression modulation in Koreans with systemic lupus erythematosus. Sci Rep 9(1):18565

    Article  CAS  Google Scholar 

  158. Lagos-Cabré R et al (2019) Connexins in astrocyte migration. Front Pharmacol 10:1546

    Article  Google Scholar 

  159. Hong S et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352(6286):712–716

    Article  CAS  Google Scholar 

  160. Yuan T, Orock A, Greenwood-Van Meerveld B (2021) Amygdala microglia modify neuronal plasticity via complement C1q/C3-CR3 signaling and contribute to visceral pain in a rat model. Am J Physiol Gastrointest Liver Physiol 320(6):1092

    Article  Google Scholar 

  161. Sudom A et al (2018) Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2. J Biol Chem 293(32):12634–12646

    Article  CAS  Google Scholar 

  162. Bailey CC, DeVaux LB, Farzan M (2015) The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J Biol Chem 290(43):26033–26042

    Article  CAS  Google Scholar 

  163. Poliani PL et al (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 125(5):2161–2170

    Article  Google Scholar 

  164. Piras S et al (2016) RAGE Expression and ROS generation in neurons: differentiation versus damage. Oxid Med Cell Longev 2016:9348651

    Article  CAS  Google Scholar 

  165. Zhang S et al (2020) HMGB1/RAGE axis mediates stress-induced RVLM neuroinflammation in mice via impairing mitophagy flux in microglia. J Neuroinflammation 17(1):15

    Article  CAS  Google Scholar 

  166. Teissier T, Boulanger É (2019) The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging. Biogerontology 20(3):279–301

    Article  CAS  Google Scholar 

  167. Sajithlal G et al (2002) Receptor for advanced glycation end products plays a more important role in cellular survival than in neurite outgrowth during retinoic acid-induced differentiation of neuroblastoma cells. J Biol Chem 277(9):6888–6897

    Article  CAS  Google Scholar 

  168. Jones RS et al (2013) Amyloid-β-induced astrocytic phagocytosis is mediated by CD36, CD47 and RAGE. J Neuroimmune Pharmacol 8(1):301–311

    Article  Google Scholar 

  169. Cai Z et al (2016) Role of RAGE in Alzheimer’s disease. Cell Mol Neurobiol 36(4):483–495

    Article  CAS  Google Scholar 

  170. Jiang X et al (2018) RAGE and its emerging role in the pathogenesis of Parkinson’s disease. Neurosci Lett 672:65–69

    Article  CAS  Google Scholar 

  171. Huang L et al (2020) The activation of phosphatidylserine/CD36/TGF-β1 pathway prior to surgical brain injury attenuates neuroinflammation in rats. Oxid Med Cell Longev 2020:4921562

    Article  Google Scholar 

  172. Banesh S, Ramakrishnan V, Trivedi V (2018) Mapping of phosphatidylserine recognition region on CD36 ectodomain. Arch Biochem Biophys 660:1–10

    Article  CAS  Google Scholar 

  173. Rawji KS et al (2020) Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system. Acta Neuropathol 139(5):893–909

    Article  CAS  Google Scholar 

  174. Cusulin C et al (2012) Embryonic stem cell-derived neural stem cells fuse with microglia and mature neurons. Stem Cells 30(12):2657–2671

    Article  CAS  Google Scholar 

  175. Dobri AM et al (2021) CD36 in Alzheimer’s Disease: An Overview of Molecular Mechanisms and Therapeutic Targeting. Neuroscience 453:301–311

    Article  CAS  Google Scholar 

  176. Grajchen E et al (2020) CD36-mediated uptake of myelin debris by macrophages and microglia reduces neuroinflammation. J Neuroinflammation 17(1):224

    Article  CAS  Google Scholar 

  177. Kay JG, Grinstein S (2013) Phosphatidylserine-mediated cellular signaling. In: Capelluto DGS (ed) lipid-mediated protein signaling. Springer, New York, pp 177–193

    Chapter  Google Scholar 

  178. Marinetti GV, Love R (1976) Differential reaction of cell membrane phospholipids and proteins with chemical probes. Chem Phys Lipid 16(4):239–254

    Article  CAS  Google Scholar 

  179. Boon JM, Smith BD (2002) Chemical control of phospholipid distribution across bilayer membranes. Med Res Rev 22(3):251–281

    Article  CAS  Google Scholar 

  180. Daleke DL (2003) Regulation of transbilayer plasma membrane phospholipid asymmetry (vol 44, pg 233, 2003). J Lipid Res 44(12):2429–2429

    CAS  Google Scholar 

  181. Martin OC, Pagano RE (1987) Transbilayer movement of fluorescent analogs of phosphatidylserine and phosphatidylethanolamine at the plasma membrane of cultured cells. Evidence for a protein-mediated and ATP-dependent process(es). J Biol Chem 262(12):5890–8

    Article  CAS  Google Scholar 

  182. Haldar S, Chattopadhyay A (2013) Application of NBD-labeled lipids in membrane and cell biology. In: Mély Y, Duportail G (eds) fluorescent methods to study biological membranes. Berlin Heidelberg, Springer, pp 37–50

    Google Scholar 

  183. Saijo S et al (2006) Discrimination of early and late apoptotic cells by NBD-phosphatidylserine-labelling and time-lapse observation of phagocytosis of apoptotic cells by macrophages. The Journal of Biochemistry 141(3):301–307

    Article  Google Scholar 

  184. Chattopadhyay A, London E (1987) Parallax method for direct measurement of membrane penetration depth utilizing fluorescence quenching by spin-labeled phospholipids. Biochemistry 26(1):39–45

    Article  CAS  Google Scholar 

  185. Reutelingsperger CP, van Heerde WL (1997) Annexin V, the regulator of phosphatidylserine-catalyzed inflammation and coagulation during apoptosis. Cell Mol Life Sci 53(6):527–532

    Article  CAS  Google Scholar 

  186. Kang TH et al (2020) Annexin A5 as an immune checkpoint inhibitor and tumor-homing molecule for cancer treatment. Nat Commun 11(1):1137

    Article  CAS  Google Scholar 

  187. Peng B et al (2014) Annexin A5 as a potential marker in tumors. Clin Chim Acta 427:42–48

    Article  CAS  Google Scholar 

  188. van Genderen HO et al (2008) Extracellular annexin A5: functions of phosphatidylserine-binding and two-dimensional crystallization. Biochim Biophys Acta 1783(6):953–963

    Article  Google Scholar 

  189. Olofsson A, Mallouh V, Brisson A (1994) Two-dimensional structure of membrane-bound annexin V at 8 A resolution. J Struct Biol 113(3):199–205

    Article  CAS  Google Scholar 

  190. Jacob T et al (2002) Modulation of cytosolic Ca(2+) concentration in airway epithelial cells by Pseudomonas aeruginosa. Infect Immun 70(11):6399–6408

    Article  CAS  Google Scholar 

  191. Calderon F, Kim HY (2008) Detection of intracellular phosphatidylserine in living cells. J Neurochem 104(5):1271–1279

    Article  CAS  Google Scholar 

  192. Liu T et al (2009) Detection of apoptosis based on the interaction between annexin V and phosphatidylserine. Anal Chem 81(6):2410–2413

    Article  CAS  Google Scholar 

  193. van Engeland M et al (1998) Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. Cytometry 31(1):1–9

    Article  Google Scholar 

  194. Kim YE et al (2010) Engineering a polarity-sensitive biosensor for time-lapse imaging of apoptotic processes and degeneration. Nat Methods 7(1):67–73

    Article  CAS  Google Scholar 

  195. Li T et al (2021) Phospholipid-flippase chaperone CDC50A is required for synapse maintenance by regulating phosphatidylserine exposure. EMBO J 40(21):15

    Article  Google Scholar 

  196. Kolodgie FD et al (2003) Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V - A technique with potential for noninvasive imaging of vulnerable plaque. Circulation 108(25):3134–3139

    Article  CAS  Google Scholar 

  197. Kim H et al (2020) A quenched Annexin V-fluorophore for the real-time fluorescence imaging of apoptotic processes in vitro and in vivo. Adv Sci 7(24):12

    Google Scholar 

  198. Smith BA et al (2011) In vivo targeting of cell death using a synthetic fluorescent molecular probe. Apoptosis 16(7):722–731

    Article  Google Scholar 

  199. Smith BA et al (2012) Multicolor fluorescence imaging of traumatic brain injury in a cryolesion mouse model. ACS Chem Neurosci 3(7):530–537

    Article  CAS  Google Scholar 

  200. Chan MM et al (2015) Non-invasive in vivo imaging of arthritis in a collagen-induced murine model with phosphatidylserine-binding near-infrared (NIR) dye. Arthritis Res Ther 17(1):50

    Article  Google Scholar 

  201. Mazzoni F et al (2019) Non-invasive in vivo fluorescence imaging of apoptotic retinal photoreceptors. Sci Rep 9(1):1590

    Article  Google Scholar 

  202. Yeung T et al (2008) Membrane phosphatidylserine regulates surface charge and protein localization. Science 319(5860):210–213

    Article  CAS  Google Scholar 

  203. Krappa R et al (1999) Evectins: Vesicular proteins that carry a pleckstrin homology domain and localize to post-Golgi membranes. Proc Natl Acad Sci USA 96(8):4633–4638

    Article  CAS  Google Scholar 

  204. Uchida Y et al (2011) Intracellular phosphatidylserine is essential for retrograde membrane traffic through endosomes. Proc Natl Acad Sci USA 108(38):15846–15851

    Article  CAS  Google Scholar 

  205. Hasegawa J et al (2021) A role of phosphatidylserine in the function of recycling endosomes. Front Cell Dev Biol 9:8

    Article  Google Scholar 

  206. Chung J et al (2015) PI4P/phosphatidylserine countertransport at ORP5-and ORP8-mediated ER-plasma membrane contacts. Science 349(6246):428–432

    Article  CAS  Google Scholar 

  207. Li YE et al (2021) TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine. J Cell Biol 220(6):e202103105

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would apologize to authors whose relevant research was not cited due to the space limitation.

Funding

This work was sponsored by Basic Research Program of Shanghai (20JC1412200), The National Key Research and Development Program of China (2020YFA0113000, 2018YFA0109800), and National Natural Science Foundation of China (81971324).

Author information

Authors and Affiliations

  1. School of Life Sciences, Shanghai University, Shanghai, China

    Junyi Zhuang, Yuchen Zhang, Huichen Shu, Shibo Zhang, Wanwei Zhao & Jiao Wang

  2. Banner Ocotillo Medical Center, 1405 S Alma School Rd, Chandler, AZ, 85286, USA

    Natalie Ward

Authors
  1. Junyi Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuchen Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huichen Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shibo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wanwei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Natalie Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jiao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors reviewed the literature and wrote first drafts of the respective sections. J.W., J.Z., Y.Z., H.S., and N. W. integrated the sections to form the final version of the manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Jiao Wang.

Ethics declarations

Ethics Approval

Not applicable.

Informed Consent

Not applicable.

Consent for Publication

Not applicable.

Institutional Review Board Statement

The authors declare no conflict of interest.

Conflict of Interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhuang, J., Zhang, Y., Shu, H. et al. Phosphatidylserine in the Nervous System: Cytoplasmic Regulator of the AKT and PKC Signaling Pathways and Extracellular “Eat-Me” Signal in Microglial Phagocytosis. Mol Neurobiol 60, 1050–1066 (2023). https://doi.org/10.1007/s12035-022-03133-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-022-03133-6

Keywords

Search

Navigation