TPPB (α-Amyloid Precursor Protein Modulator)はベンゾラクタム由来の細胞通過性タンパク質キナーゼC (PKC)活性化剤(Ki = 11.9nM)である[1]。TPPBはα-セクレターゼの活性を増やし、sAPPαの分泌を増やし、同時にβ-セクレターゼ(BACE1)の発見とAβ40断片の放出を減らした[2-3]。TPPBは主にアルツハイマー病の治療に使われる[4]。
SH-SY5Y細胞で、TPPB (0.1-100nM；3時間)はsAPPαの細胞分泌を誘発する[5]。PC12細胞で、TPPB (0-10μM；3時間)は全長APPの発見を影響せずに、sAPPαの分泌を促進した[6]。
実験性自己免疫脳脊髄炎（EAE）マウスモデルで、TPPB (50nmol/kg；腹腔内注射；21日間；週に三日)は神経学的欠損を軽減できる[7]。
References:
[1]. Kozikowski A P, Nowak I, Petukhov P A, et al. New amide-bearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor protein metabolite sAPPα[J]. Journal of medicinal chemistry, 2003, 46(3): 364-373.
[2]. Yang H Q, Pan J, Ba M W, et al. New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing α‐secretase activity[J]. European Journal of Neuroscience, 2007, 26(2): 381-391.
[3]. Hong-Qi Y, Zhi-Kun S, Sheng-Di C. Current advances in the treatment of Alzheimer's disease: focused on considerations targeting Aβ and tau[J]. Translational neurodegeneration, 2012, 1(1): 21.
[4]. Yang H Q, Li X, Yang W M, et al. Neuroprotective Effects of New Protein Kinase C Activator TPPB Against Aβ25–35 Induced Neurotoxicity in PC12 Cells[J]. Neurochemical research, 2012, 37(10): 2213-2221.
[5]. Yi P, Schrott L, Castor T P, et al. Bryostatin-1 vs. TPPB: dose-dependent APP processing and PKC-α,-δ, and-ε isoform activation in SH-SY5Y neuronal cells[J]. Journal of Molecular Neuroscience, 2012, 48(1): 234-244.
[6]. Yang H Q, Pan J, Ba M W, et al. New protein kinase C activator regulates amyloid precursor protein processing in vitro by increasing α‐secretase activity[J]. European Journal of Neuroscience, 2007, 26(2): 381-391.
[7]. Shanmukha S, Godfrey W H, Gharibani P, et al. TPPB modulates PKC activity to attenuate neuroinflammation and ameliorate experimental multiple sclerosis[J]. Frontiers in Cellular Neuroscience, 2024, 18: 1373557.