Alzheimer's disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aβ, particularly neurotoxic Aβ42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aβ42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aβ generation. Our study supports the hypothesis that Aβ induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.

中文翻译：

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淀粉样蛋白斑周围的突触前营养不良的神经突是微管破裂，BACE1升高和阿尔茨海默氏病中Aβ生成增加的部位。

阿尔茨海默氏病（AD）的特征是淀粉样蛋白斑块由β-淀粉样蛋白（Aβ）肽组成，周围由肿胀的突触前营养不良性神经突包围，这些神经突由功能障碍的轴突和末端组成，这些蛋白会积聚所需的β-位淀粉样蛋白前体蛋白（APP）裂解酶（BACE1）用于生成Aβ。控制突触前营养不良性神经突形成的细胞和分子机制尚不清楚，阐明这些过程可能导致新的AD治疗策略。先前的研究表明，Aβ可能会破坏微管，我们认为这在突触前营养不良的发展中起着至关重要的作用。为了进一步研究这一点，在这里我们评估了在体外和体内突触前营养不良性神经突形成过程中Aβ（特别是神经毒性Aβ42）对微管的作用。初级神经元的活细胞成像显示，暴露于Aβ42低聚物会引起静脉曲张和串珠状神经突，并引起广泛的微管破坏，并抑制顺行和逆行运输。在AD患者的大脑切片和5XFAD淀粉样蛋白病理的转基因小鼠模型中，淀粉样蛋白斑周围BACE1升高的营养不良性神经突晕表现出微管蛋白异常积聚或空洞。在超微结构水平上，斑块周围营养不良明显缺乏微管，并充满了类似于自噬中间体的多层囊泡。微管运动蛋白，驱动蛋白和动力蛋白以及其他神经元蛋白异常定位在斑块周围营养不良中。无效的前蛋白酶D也积聚在斑块周围营养不良中，表明溶酶体功能降低。最重要的是，斑块周围营养不良中的BACE1积累导致APP和Aβ生成的BACE1裂解增加。我们的研究支持以下假设：Aβ在围绕斑块的突触前营养不良性神经突中诱导微管破坏，从而损害轴突运输并导致BACE1积累和AD淀粉样蛋白病态恶化。