Kuhn Thomas B, Minamide Laurie S, Tahtamouni Lubna H, Alderfer Sydney A, Walsh Keifer P, Shaw Alisa E, Yanouri Omar, Haigler Henry J, Ruff Michael R, Bamburg James R
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA.
Department of Biology and Biotechnology, Faculty of Science, The Hashemite University, Zarqa 13133, Jordan.
Biomedicines. 2024 Jan 1;12(1):93. doi: 10.3390/biomedicines12010093.
Synapse loss is the principal cause of cognitive decline in Alzheimer's disease (AD) and related disorders (ADRD). Synapse development depends on the intricate dynamics of the neuronal cytoskeleton. Cofilin, the major protein regulating actin dynamics, can be sequestered into cofilactin rods, intra-neurite bundles of cofilin-saturated actin filaments that can disrupt vesicular trafficking and cause synaptic loss. Rods are a brain pathology in human AD and mouse models of AD and ADRD. Eliminating rods is the focus of this paper. One pathway for rod formation is triggered in ~20% of rodent hippocampal neurons by disease-related factors (e.g., soluble oligomers of Amyloid-β (Aβ)) and requires cellular prion protein (PrP), active NADPH oxidase (NOX), and cytokine/chemokine receptors (CCRs). FDA-approved antagonists of CXCR4 and CCR5 inhibit Aβ-induced rods in both rodent and human neurons with effective concentrations for 50% rod reduction (EC) of 1-10 nM. Remarkably, two D-amino acid receptor-active peptides (RAP-103 and RAP-310) inhibit Aβ-induced rods with an EC of ~1 pM in mouse neurons and ~0.1 pM in human neurons. These peptides are analogs of D-Ala-Peptide T-Amide (DAPTA) and share a pentapeptide sequence (TTNYT) antagonistic to several CCR-dependent responses. RAP-103 does not inhibit neuritogenesis or outgrowth even at 1 µM, >10-fold above its EC. N-terminal methylation, or D-Thr to D-Ser substitution, decreases the rod-inhibiting potency of RAP-103 by 10-fold, suggesting high target specificity. Neither RAP peptide inhibits neuronal rod formation induced by excitotoxic glutamate, but both inhibit rods induced in human neurons by several PrP/NOX pathway activators (Aβ, HIV-gp120 protein, and IL-6). Significantly, RAP-103 completely protects against Aβ-induced loss of mature and developing synapses and, at 0.1 nM, reverses rods in both rodent and human neurons (T ~ 3 h) even in the continuous presence of Aβ. Thus, this orally available, brain-permeable peptide should be highly effective in reducing rod pathology in multifactorial neurological diseases with mixed proteinopathies acting through PrP/NOX.
突触丧失是阿尔茨海默病（AD）及相关疾病（ADRD）认知衰退的主要原因。突触发育依赖于神经元细胞骨架的复杂动态变化。肌动蛋白解聚因子（Cofilin）是调节肌动蛋白动态变化的主要蛋白质，可被隔离到肌动蛋白解聚因子杆状结构中，这是一种由富含肌动蛋白解聚因子的肌动蛋白丝组成的神经突内束状结构，会破坏囊泡运输并导致突触丧失。杆状结构是人类AD以及AD和ADRD小鼠模型中的一种脑部病理特征。消除杆状结构是本文的重点。约20%的啮齿动物海马神经元中，疾病相关因素（如淀粉样β蛋白（Aβ）的可溶性寡聚体）会触发杆状结构形成的一条途径，该途径需要细胞朊蛋白（PrP）、活性烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOX）和细胞因子/趋化因子受体（CCR）。美国食品药品监督管理局（FDA）批准的CXCR4和CCR5拮抗剂可抑制啮齿动物和人类神经元中Aβ诱导的杆状结构形成，半数抑制浓度（EC）为1 - 10 nM。值得注意的是，两种D - 氨基酸受体活性肽（RAP - 103和RAP - 310）在小鼠神经元中的半数抑制浓度约为1 pM，在人类神经元中约为0.1 pM，可抑制Aβ诱导的杆状结构形成。这些肽是D - 丙氨酸 - 肽T - 酰胺（DAPTA）的类似物，共享一个五肽序列（TTNYT），对几种CCR依赖性反应具有拮抗作用。即使在1 μM浓度下，RAP - 103也不抑制神经突发生或生长，该浓度比其半数抑制浓度高10倍以上。N端甲基化或D - 苏氨酸到D - 丝氨酸的取代会使RAP - 103抑制杆状结构的效力降低10倍，表明其具有高度的靶点特异性。两种RAP肽都不抑制兴奋性毒性谷氨酸诱导的神经元杆状结构形成，但都能抑制几种PrP/NOX途径激活剂（Aβ、HIV - gp120蛋白和白细胞介素 - 6）在人类神经元中诱导的杆状结构形成。重要的是，RAP - 1与Aβ诱导的成熟和发育中突触丧失完全保护作用，在0.1 nM浓度下，即使在Aβ持续存在的情况下，也能在啮齿动物和人类神经元中逆转杆状结构（T约3小时）。因此，这种口服可用、可透过血脑屏障的肽在减少通过PrP/NOX起作用且具有混合蛋白病变的多因素神经疾病中的杆状结构病理方面应该非常有效。
