Amyloid precursor protein and amyloid precursor-like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons

Phan H. Truong, Giuseppe D. Ciccotosto, Tobias D. Merson, Loredana Spoerri, Mun Joo Chuei, Margaret Ayers, Yao Lulu Xing, Ben Emery, Roberto Cappai

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild-type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2-KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP-KO mice were less susceptible to cuprizone-induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination.

Original languageEnglish
Pages (from-to)525-538
Number of pages14
JournalGLIA
Volume67
Issue number3
DOIs
Publication statusPublished - Mar 2019

Keywords

  • amyloid precursor protein
  • amyloid precursor-like protein
  • cuprizone
  • knockout
  • myelin

Cite this

Truong, Phan H. ; Ciccotosto, Giuseppe D. ; Merson, Tobias D. ; Spoerri, Loredana ; Chuei, Mun Joo ; Ayers, Margaret ; Xing, Yao Lulu ; Emery, Ben ; Cappai, Roberto. / Amyloid precursor protein and amyloid precursor-like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons. In: GLIA. 2019 ; Vol. 67, No. 3. pp. 525-538.
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Amyloid precursor protein and amyloid precursor-like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons. / Truong, Phan H.; Ciccotosto, Giuseppe D.; Merson, Tobias D.; Spoerri, Loredana; Chuei, Mun Joo; Ayers, Margaret; Xing, Yao Lulu; Emery, Ben; Cappai, Roberto.

In: GLIA, Vol. 67, No. 3, 03.2019, p. 525-538.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Ciccotosto, Giuseppe D.

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AB - The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild-type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2-KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP-KO mice were less susceptible to cuprizone-induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination.

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