Naderi Yeganeh Pourya, Kwak Sang Su, Jorfi Mehdi, Koler Katjuša, Kalatturu Thejesh, von Maydell Djuna, Liu Zhiqing, Guo Kevin, Choi Younjung, Park Joseph, Abarca Nelson, Bakiasi Grisilda, Cetinbas Murat, Sadreyev Ruslan, Griciuc Ana, Quinti Luisa, Choi Se Hoon, Xia Weiming, Tanzi Rudolph E, Hide Winston, Kim Doo Yeon
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, USA.
Neuron. 2025 Jan 22;113(2):205-224.e8. doi: 10.1016/j.neuron.2024.10.029. Epub 2024 Nov 27.
Alzheimer's disease (AD) presents a complex pathological landscape, posing challenges to current therapeutic strategies that primarily target amyloid-β (Aβ). Using a novel integrative pathway activity analysis (IPAA), we identified 83 dysregulated pathways common between both post-mortem AD brains and three-dimensional AD cellular models showing robust Aβ42 accumulation. p38 mitogen-activated protein kinase (MAPK) was the most upregulated common pathway. Active p38 MAPK levels increased in the cellular models, human brains, and 5XFAD mice and selectively localized to presynaptic dystrophic neurites. Unbiased phosphoproteomics confirmed increased phosphorylation of p38 MAPK substrates. Downstream activation of MAPK-activated protein kinase 2 (MK2) plays a crucial role in Aβ42-p38 MAPK-mediated tau pathology. Therapeutic targeting of the p38 MAPK-MK2 axis with selective inhibitors significantly reduced Aβ42-driven tau pathology and neuronal loss. IPAA prioritizes the best models to derisk target-drug discovery by integrating human tissue gene expression with functional readouts from cellular models, enabling the identification and validation of high-confidence AD therapeutic targets.
阿尔茨海默病（AD）呈现出复杂的病理格局，给当前主要针对淀粉样β蛋白（Aβ）的治疗策略带来了挑战。通过一种新型的综合通路活性分析（IPAA），我们在死后AD大脑和显示出强大Aβ42积累的三维AD细胞模型之间鉴定出83条失调的共同通路。p38丝裂原活化蛋白激酶（MAPK）是上调最明显的共同通路。在细胞模型、人类大脑和5XFAD小鼠中，活性p38 MAPK水平升高，并选择性地定位于突触前营养不良性神经突。非偏向性磷酸化蛋白质组学证实了p38 MAPK底物磷酸化增加。MAPK活化蛋白激酶2（MK2）的下游激活在Aβ42-p38 MAPK介导的tau病理中起关键作用。用选择性抑制剂对p38 MAPK-MK2轴进行治疗性靶向显著减少了Aβ42驱动的tau病理和神经元损失。IPAA通过将人类组织基因表达与细胞模型的功能读数相结合，对最佳模型进行优先排序，以降低靶点药物发现的风险，从而能够识别和验证高可信度的AD治疗靶点。
