Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
Acta Neuropathol. 2018 Dec;136(6):901-917. doi: 10.1007/s00401-018-1922-z. Epub 2018 Oct 25.
Growing evidence gathered from transgenic animal models of Alzheimer's disease (AD) indicates that the intraneuronal accumulation of amyloid-β (Aβ) peptides is an early event in the AD pathogenesis, producing cognitive deficits before the deposition of insoluble plaques. Levels of soluble Aβ are also a strong indicator of synaptic deficits and concurrent AD neuropathologies in post-mortem AD brain; however, it remains poorly understood how this soluble amyloid pool builds within the brain in the decades leading up to diagnosis, when a patient is likely most amenable to early therapeutic interventions. Indeed, characterizing early intracellular Aβ accumulation in humans has been hampered by the lack of Aβ-specific antibodies, variability in the quality of available human brain tissue and the limitations of conventional microscopy. We therefore sought to investigate the development of the intraneuronal Aβ pathology using extremely high-quality post-mortem brain material obtained from a cohort of non-demented subjects with short post-mortem intervals and processed by perfusion-fixation. Using well-characterized monoclonal antibodies, we demonstrate that the age-dependent intraneuronal accumulation of soluble Aβ is pervasive throughout the entorhinal cortex and hippocampus, and that this phase of the amyloid pathology becomes established within AD-vulnerable regions before the deposition of Aβ plaques and the formation of tau neurofibrillary tangles. We also show for the first time in post-mortem human brain that Aβ oligomers do in fact accumulate intraneuronally, before the formation of extracellular plaques. Finally, we validated the origin of the Aβ-immunopositive pool by resolving Aβ- and APP/CTF-immunoreactive sites using super resolution structured illumination microscopy. Together, these findings indicate that the lifelong accrual of intraneuronal Aβ may be a potential trigger for downstream AD-related pathogenic events in early disease stages.
越来越多的阿尔茨海默病（AD）转基因动物模型研究证据表明，淀粉样β（Aβ）肽在神经元内的积累是 AD 发病机制中的早期事件，在不溶性斑块沉积之前就会产生认知缺陷。可溶性 Aβ 水平也是 AD 患者死后大脑中突触缺陷和并发 AD 神经病理学的一个强有力指标；然而，人们对这种可溶性淀粉样蛋白池在诊断前几十年内在大脑中是如何积累的仍知之甚少，因为此时患者最有可能接受早期治疗干预。事实上，由于缺乏 Aβ 特异性抗体、现有人类脑组织质量的可变性以及传统显微镜的局限性，人们对人类早期细胞内 Aβ 积累的特征描述受到了阻碍。因此，我们试图使用从一组非痴呆、死后间隔时间短并通过灌注固定处理的受试者中获得的超高质量的死后脑组织材料来研究神经元内 Aβ 病理学的发展。使用经过充分特征描述的单克隆抗体，我们证明了可溶性 Aβ 随年龄增长在整个内嗅皮层和海马中的神经元内积累是普遍存在的，并且在 Aβ 斑块沉积和 tau 神经原纤维缠结形成之前，这种淀粉样病理的阶段就在 AD 易损区域内建立。我们还首次在死后人类大脑中证明，Aβ 寡聚体实际上在细胞外斑块形成之前就会在神经元内积累。最后，我们通过使用超分辨率结构光照明显微镜解析 Aβ 和 APP/CTF-免疫反应性位点，验证了 Aβ-免疫阳性池的起源。综上所述，这些发现表明，神经元内 Aβ 的终身积累可能是早期疾病阶段 AD 相关致病事件的潜在触发因素。
