Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.
Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer's disease.
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DOI：
10.1007/s00401-016-1558-9
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发表时间：
2016-08
影响因子：
12.7
通讯作者：
Vassar R
中科院分区：
文献类型：
--
作者：
Sadleir KR;Kandalepas PC;Buggia-Prévot V;Nicholson DA;Thinakaran G;Vassar R
阿尔茨海默氏病 (AD) 的特征是由 β-淀粉样蛋白 (Aβ) 肽组成的淀粉样斑块，周围有肿胀的突触前营养不良神经突，这些神经突由功能失调的轴突和末端组成，积累了 Aβ 生成所需的 β 位点淀粉样蛋白前体蛋白 (APP) 裂解酶 (BACE1)。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，阐明这些过程可能会带来新的 AD 治疗策略。先前的研究表明 Aβ 可能会破坏微管，我们假设微管在突触前营养不良的发生中起着关键作用。为了进一步研究这一点，我们在这里评估了 Aβ，特别是神经毒性 Aβ42，在体外和体内突触前营养不良性神经突形成过程中对微管的影响。原代神经元的活细胞成像显示，暴露于 Aβ42 寡聚物会导致静脉曲张和串珠状神经突，并伴有广泛的微管破坏，并抑制顺行和逆行运输。在 AD 患者和淀粉样蛋白病理学 5XFAD 转基因小鼠模型的脑切片中，淀粉样斑块周围 BACE1 升高的营养不良性神经突晕表现出异常的微管蛋白积聚或空隙。在超微结构水平上，斑块周围营养不良明显缺乏微管，并充满类似于自噬中间体的多层囊泡。微管马达蛋白、驱动蛋白和动力蛋白以及其他神经元蛋白异常定位于斑块周围营养不良。无活性的组织蛋白酶 D 原也在斑块周围营养不良中积聚，表明溶酶体功能降低。最重要的是，斑块周围营养不良中 BACE1 的积累导致 BACE1 对 APP 和 Aβ 生成的裂解增加。我们的研究支持这样的假设：Aβ 会诱导斑块周围的突触前营养不良神经突中的微管破坏，从而损害轴突运输并导致 BACE1 积累和 AD 中淀粉样蛋白病理学恶化。本文的在线版本 (doi:10.1007/s00401-016-1558-9) 包含补充材料，可供授权用户使用。
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. The online version of this article (doi:10.1007/s00401-016-1558-9) contains supplementary material, which is available to authorized users.