title: Reversing hypomyelination in BACE1-null mice with Akt-DD overexpression.
abstract: β-Site amyloid precursor protein convertase enzyme 1 (BACE1), a type I transmembrane aspartyl protease required to cleave amyloid precursor protein for releasing a toxic amyloid peptide, also cleaves type I and type III neuregulin-1 (Nrg-1). BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination if injured. In BACE1-null mice, the abolished cleavage of neuregulin-1 by BACE1 is speculated to cause reduced myelin sheath thickness in both the central nervous system and peripheral nervous system because reduced cleavage of Nrg-1 correlates with reduced Akt phosphorylation, a downstream signaling molecule of the Nrg-1/ErbB pathway. Here we tested specifically whether increasing Akt activity alone in oligodendrocytes would be sufficient to reverse the hypomyelination phenotype in BACE1-null mice. BACE1-null mice were bred with transgenic mice expressing constitutively active Akt (Akt-DD; mutations with D(308)T and D(473)S) in oligodendrocytes. Relative to littermate BACE1-null controls, BACE1(-/-)/Akt-DD mice exhibited enhanced expression of myelin basic protein and promoter of proteolipid protein. The elevated expression of myelin proteins correlated with a thicker myelin sheath in optic nerves; comparison of quantified g ratios with statistic significance was used to confirm this reversion. However, it appeared that myelin sheath thickness in the sciatic nerves was not increased in BACE1(-/-)/Akt-DD mice, as the g ratio was not significantly different from the control. Hence, increased Akt activity in BACE1-null myelinating cells only compensates for the loss of BACE1 activity in the central nervous system, which is consistent with the observation that overexpression of Akt-DD in Schwann cells did not induce hypermyelination. Our results suggest that signaling activity other than Akt may also contribute to proper myelination in peripheral nerves.
authors: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Xiangyou
authors: X
authors: Hu
authors: Rita
authors: R
authors: Schlanger
authors: Wanxia
authors: W
authors: He
authors: Wendy B
authors: WB
authors: Macklin
authors: Riqiang
authors: R
authors: Yan
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000096:biosynthesis*; D018991:Myelin Proteolipid Protein / Q000096:biosynthesis*; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse