Masking the transmembrane region of the amyloid β precursor protein as a safe means to lower amyloid β production.
Masking the transmembrane region of the amyloid β precursor protein as a safe means to lower amyloid β production.
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DOI：
10.1002/trc2.12428
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发表时间：
2023-10
影响因子：
4.8
通讯作者：
Ulmschneider, Martin B
中科院分区：
文献类型：
--
作者：
Khan, Ayesha;Killick, Richard;Wirth, Daniel;Hoogland, Dominique;Hristova, Kalina;Ulmschneider, Jakob P;King, Christopher R;Ulmschneider, Martin B
降低大脑中可溶和不可溶形式的淀粉样β蛋白(Aβ)水平仍然是大多数针对阿尔茨海默病(AD)的治疗方法的主要目标。然而，到目前为止，还没有任何治疗方法使患者受益，最有希望的候选药物的临床试验通常由于显著的不良反应而失败。这突出了需要更安全和更有选择性的方法来靶向和调节Aβ的生物发生。多肽技术已经发展到可以可靠地合成、纯化和传递曾经具有挑战性的疏水序列。这为针对与疾病相关的膜过程开辟了新的途径。在这里，我们采用了原子细节分子动力学(MD)模拟、活细胞Förster共振能量转移(FRET)和体外分析相结合的方法来阐明以Aβ前体蛋白(APP)为靶点的膜活性多肽的原子细节动力学、分子机制以及细胞活性和选择性。我们证明，使用APP封闭肽(APPOP)可以选择性地下调Aβ的生物发生。在原代培养的大鼠皮质神经细胞中，APPOP抑制Aβ的产生呈剂量依赖性，对外源性APP的平均抑制浓度(IC_(50))为450nM，对内源性APP的平均抑制浓度(IC_(50))为50nM。APPOP不影响Notch-1的γ分泌酶裂解，也不对原代培养的大鼠神经元表现出毒性，提示APP选择性地保护APP不被蛋白质降解。针对阿尔茨海默病的药物需要及早并持续很长时间，以防止临床症状的出现。这需要能够精确地针对Aβ的产生，并且不影响关键细胞酶的活性，例如其他底物的γ分泌酶。多肽为精确靶向关键途径提供了一种强大的方法，从而降低了不良反应的风险。在这里，我们表明，保护APP免受蛋白质降解处理提供了一条安全且特异地降低Aβ负担的有希望的途径。特别是，我们证明了淀粉样蛋白通路可以直接和特定地作为靶点。这降低了偏离目标效应的风险，并为安全的预防性治疗铺平了道路。
Reducing brain levels of both soluble and insoluble forms of amyloid beta (Aβ) remains the primary goal of most therapies that target Alzheimer's disease (AD). However, no treatment has so far resulted in patient benefit, and clinical trials of the most promising drug candidates have generally failed due to significant adverse effects. This highlights the need for safer and more selective ways to target and modulate Aβ biogenesis. Peptide technology has advanced to allow reliable synthesis, purification, and delivery of once‐challenging hydrophobic sequences. This is opening up new routes to target membrane processes associated with disease. Here we deploy a combination of atomic detail molecular dynamics (MD) simulations, living‐cell Förster resonance energy transfer (FRET), and in vitro assays to elucidate the atomic‐detail dynamics, molecular mechanisms, and cellular activity and selectivity of a membrane‐active peptide that targets the Aβ precursor protein (APP). We demonstrate that Aβ biogenesis can be downregulated selectively using an APP occlusion peptide (APPOP). APPOP inhibits Aβ production in a dose‐dependent manner, with a mean inhibitory concentration (IC50) of 450 nM toward exogenous APP and 50 nM toward endogenous APP in primary rat cortical neuronal cultures. APPOP does not impact the γ‐secretase cleavage of Notch‐1, or exhibit toxicity toward cultured primary rat neurons, suggesting that it selectively shields APP from proteolysis. Drugs targeting AD need to be given early and for very long periods to prevent the onset of clinical symptoms. This necessitates being able to target Aβ production precisely and without affecting the activity of key cellular enzymes such as γ‐secretase for other substrates. Peptides offer a powerful way for targeting key pathways precisely, thereby reducing the risk of adverse effects. Here we show that protecting APP from proteolytic processing offers a promising route to safely and specifically lower Aβ burden. In particular, we show that the amyloid pathway can be targeted directly and specificically. This reduces the risk of off‐target effects and paves the way for a safe prophylactic treatment.
影响因子：
2.4
作者：
Gorman PM;Kim S;Guo M;Melnyk RA;McLaurin J;Fraser PE;Bowie JU;Chakrabartty A
通讯作者：
Chakrabartty A