Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY10314, USA.
Acta Neuropathol Commun. 2020 Apr 28;8(1):58. doi: 10.1186/s40478-020-00923-8.
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.
自闭症是一种非常复杂的病因学神经发育障碍，最常见，与细胞内稳态机制的失调有关，包括淀粉样前体蛋白 (APP) 的处理。APP 处理的产物——N 端截断的淀粉样β肽 (N-tr-Aβ) 物质——在自闭症患者的大脑皮层、小脑和皮质下结构的神经元和神经胶质中积累。这一过程在神经元中与氧化应激增加有关。由于仅在前额叶皮质的一小部分神经元中检测到异常高水平的 N-tr-Aβ，我们应用免疫细胞化学染色和共聚焦显微镜在特发性和 15 号染色体 q11.2-q13 重复（dup-15）自闭症的尸检脑组织中，测量细胞和突触中的 N-tr-Aβ 负荷，并鉴定受这些病理生理过程影响的神经元亚群。在自闭症中积累的肽是 N 端截断的；因此，我们产生了一种针对 N 端氨基酸 11 截断的 Aβ的新抗体，该抗体被修饰为焦谷氨酸，以评估这种肽在自闭症中的存在和分布。我们还定量和表征了自闭症和对照冷冻脑组织样本中 Aβ-免疫反应性肽的寡聚化模式。我们提供了形态学证据，即在特发性和 dup-15 自闭症中，具有和不具有 N 端焦谷氨酸-11 修饰的 N-tr-Aβ 的积累主要影响表达 GABA 能神经元的 parvalbumin 亚群。N-tr-Aβ 肽在神经元的细胞质和细胞核以及 GABA 能突触中积累。免疫印迹在冷冻皮层样本中检测到具有 C 端 40 和 42 的 Aβ 肽，以 18-24kD 和 32-34kD 的分子大小的二聚体和复合物的形式存在。我们提出，N-tr-Aβ 的沉积特异性地影响表达 parvalbumin 的 GABA 能神经元的功能，并导致自闭症中大脑兴奋-抑制平衡的失调。这个过程可能是新疗法的靶点。
