TPPB (α-Amyloid Precursor Protein Modulator) is a benzolactam-derived, cell-permeable protein kinase C (PKC) activator (Ki = 11.9nM) [1]. TPPB increases α-secretase activity, leading to increased secretion of sAPPα, while simultaneously decreasing β-secretase (BACE1) expression and the release of Aβ40 fragments [2-3]. TPPB is primarily used to treat Alzheimer's disease [4].
In SH-SY5Y cells, TPPB (0.1-100nM; 3h) induces cell secretion of sAPPα [5]. In PC12 cells, TPPB (0-10μM; 3h) promoted the secretion of sAPPα without affecting the expression of full-length APP [6].
In experimental autoimmune encephalomyelitis (EAE) mice model, TPPB (50nmol/kg; ip; 21d; three days a week) can alleviate the neurological deficits [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.
TPPB (α-Amyloid Precursor Protein Modulator)是一种苯并内酰胺衍生的、可渗透细胞的蛋白激酶C（PKC）激活剂（Ki = 11.9nM） [1]。TPPB可增强α-分泌酶活性，从而增加sAPPα的分泌，同时降低β-分泌酶（BACE1）的表达和Aβ40片段的释放 [2-3]。TPPB主要用于治疗阿尔茨海默病 [4]。
在SH-SY5Y细胞中，TPPB（0.1-100nM；3h）可诱导细胞分泌sAPPα [5]。在PC12细胞中，TPPB（0-10μM；3h）可促进sAPPα的分泌，但不影响全长APP的表达 [6]。
在实验性自身免疫性脑脊髓炎（EAE）小鼠模型中，TPPB（50nmol/kg；ip；21d；每周三天）可以减轻神经功能缺损 [7]。