title: Tuberous sclerosis protein 2 (TSC2) modulates CCN4 cytoprotection during apoptotic amyloid toxicity in microglia.
abstract: More than 110 million individuals will suffer from cognitive loss worldwide by the year 2050 with a majority of individuals presenting with Alzheimer's disease (AD). Yet, successful treatments for etiologies that involve β.-amyloid (Aβ.) toxicity in AD remain elusive and await novel avenues for drug development. Here we show that Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) controls the post-translational phosphorylation of Akt1, p70S6K, and AMP activated protein kinase (AMPK) to the extent that tuberous sclerosis complex 2 (TSC2) (Ser1387) phosphorylation, a target of AMPK, is decreased and TSC2 (Thr1462) phosphorylation, a target of Akt1, is increased. The ability of WISP1 to limit TSC2 activity allows WISP1 to increase the activity of p70S6K, since gene silencing of TSC2 further enhances WISP1 phosphorylation of p70S6K. However, a minimal level of TSC2 activity is necessary to modulate WISP1 cytoprotection that may require modulation of mTOR activity, since gene knockdown of TSC2 impairs the ability of WISP1 to protect microglia against apoptotic membrane phosphatidylserine (PS) exposure, nuclear DNA degradation, mitochondrial membrane depolarization, and cytochrome c release during Aβ. exposure.
authors.affiliation: Laboratory of Cellular and Molecular Signaling, New Jersey Health Sciences University, Newark, NJ 07101, USA.
authors.forename: Yan Chen
authors.initials: YC
authors.lastname: Shang
authors.forename: Zhao Zhong
authors.initials: ZZ
authors.lastname: Chong
authors.forename: Shaohui
authors.initials: S
authors.lastname: Wang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Maiese
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D055511:CCN Intercellular Signaling Proteins / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42); D045304:Cytochromes c