Computational and Translational Neuroscience Laboratory (CTNLab), Institute of Cognitive Sciences and Technologies, National Research Council, Rome, Italy.
Unit of Molecular Neurosciences, Department of Medicine, University Campus-Biomedico, Rome, Italy.
J Alzheimers Dis. 2020;77(1):275-290. doi: 10.3233/JAD-200276.
Alzheimer's disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research.
A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage).
Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients.
We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine.
Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.
阿尔茨海默病（AD）的发病机制仍部分未知。用于研究 AD 的主要概念框架是淀粉样蛋白级联假说，尽管最近的临床实验失败似乎降低了其在 AD 研究中的潜力。
临床试验失败的一个可能解释是，它们在 AD 进展中设置得太晚。最近的研究表明，腹侧被盖区（VTA）退化可能是 AD 进展（斑块前阶段）中最早发生的事件之一。
在这里，我们通过计算模型和经过患者行为和神经数据验证的计算机模拟来研究这一假设。
我们表明，VTA 退化可能导致儿茶酚胺释放的系统水平调整，引发一系列导致 AD 相关临床和病理迹象的事件。这些变化首先是由中前额驱动的 VTA 和蓝斑（去甲肾上腺素）的代偿性过度激活组成，随着 VTA 损伤的进展，儿茶酚胺释放的下调。这些过程可能会导致皮质和海马体水平的神经退行性变，因为去甲肾上腺素的神经保护作用会慢性丧失。
我们的新假设可能有助于制定更广泛的 AD 系统水平观点，这可能有助于设计早期诊断和治疗干预措施。
