Autism, the most frequent neurodevelopmental disorder of a very complex etiopathology, is associated with dysregulation of cellular homeostatic mechanisms, including processing of amyloid-β precursor protein (APP). Products of APP processing - N-terminally truncated amyloid-β peptide (N-tr-Aβ) species - are accumulated in autism in neurons and glia in the cortex, cerebellum, and subcortical structures of the brain. This process in neurons is correlated with increased oxidative stress. Because abnormally high levels of N-tr-Aβ are detected in only a fraction of neurons in the prefrontal cortex, we applied immunocytochemical staining and confocal microscopy in autopsy brain material from idiopathic and chromosome 15q11.2-q13 duplication (dup-15) autism to measure the load of N-tr-Aβ in the cells and synapses and to identify the subpopulation of neurons affected by these pathophysiological processes. The peptides accumulated in autism are N-terminally truncated; therefore, we produced a new antibody against Aβ truncated at N-terminal amino acid 11 modified to pyroglutamate to evaluate the presence and distribution of this peptide species in autism. We also quantified and characterized the oligomerization patterns of the Aβ-immunoreactive peptides in autism and control frozen brain samples. We provide morphological evidence, that in idiopathic and dup-15 autism, accumulation of N-tr-Aβ with and without pyroglutamate-11 modified N-terminus affects mainly the parvalbumin-expressing subpopulation of GABAergic neurons. N-tr-Aβ peptides are accumulated in neurons' cytoplasm and nucleus as well as in GABAergic synapses. Aβ peptides with both C-terminus 40 and 42 were detected by immunoblotting in frozen cortex samples, in the form of dimers and complexes of the molecular sizes of 18-24kD and 32-34kD. We propose that deposition of N-tr-Aβ specifically affects the functions of the parvalbumin-expressing GABAergic neurons and results in a dysregulation of brain excitatory-inhibitory homeostasis in autism. This process may be the target of new therapies.

中文翻译：

---

在特发性和dup15q11.2-q13自闭症中，表达小白蛋白的GABA能神经元中具有和不具有焦谷氨酸11修饰的N末端截短的Aβ的积累增强。

自闭症是一种非常复杂的病因病理学中最常见的神经发育障碍，与细胞稳态机制的失调有关，包括淀粉样蛋白-β前体蛋白（APP）的加工。APP处理的产物-N端截短的淀粉样β肽（N-tr-Aβ）种类-在自闭症中积聚在大脑皮层，小脑和皮层下结构的神经元和神经胶质中。神经元的这一过程与氧化应激的增加有关。由于仅在前额叶皮层的一部分神经元中检测到异常高水平的N-tr-Aβ，因此我们对特发性和15q11号染色体的尸检脑材料进行了免疫细胞化学染色和共聚焦显微镜检查。2-q13重复（dup-15）自闭症可测量细胞和突触中N-tr-Aβ的负荷，并确定受这些病理生理过程影响的神经元亚群。自闭症中积累的肽被N端截短；因此，我们生产了一种新的抗Aβ抗体，该抗体被修饰为焦谷氨酸的N末端氨基酸11截短，以评估自闭症中该肽种类的存在和分布。我们还量化和表征了自闭症和对照冰冻脑样本中Aβ免疫反应性肽的寡聚模式。我们提供了形态学证据，在特发性和dup-15自闭症中，带有和不带有焦谷氨酸11修饰的N端的N-tr-Aβ的积累主要影响表达GABA能神经元的小白蛋白。N-tr-Aβ肽在神经元中积累 细胞质和细胞核以及GABA能突触。通过免疫印迹在冷冻皮层样品中以分子大小为18-24kD和32-34kD的二聚体和复合体的形式检测到具有C端40和42的Aβ肽。我们提出，N-tr-Aβ的沉积特别影响表达小白蛋白的GABA能神经元的功能，并导致自闭症中脑兴奋性抑制稳态的失调。该过程可能是新疗法的目标。我们提出，N-tr-Aβ的沉积特别影响表达小白蛋白的GABA能神经元的功能，并导致自闭症中脑兴奋性抑制稳态的失调。该过程可能是新疗法的目标。我们提出，N-tr-Aβ的沉积特别影响表达小白蛋白的GABA能神经元的功能，并导致自闭症中脑兴奋性抑制稳态的失调。该过程可能是新疗法的目标。