Wood Jack I, Dulewicz Maciej, Szadziewska Alicja, Weiner Sophia, Ge Junyue, Stringer Katie, Desai Sneha, Fenson Lydia, Piotrowska Diana, Brinkmalm Gunnar, Koutarapu Srinivas, Hajar Haady B, Blennow Kaj, Zetterberg Henrik, Cummings Damian M, Savas Jeffrey N, Edwards Frances A, Hanrieder Jörg
Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom.
Nat Commun. 2025 Sep 1;16(1):8170. doi: 10.1038/s41467-025-63328-y.
Understanding how amyloid beta (Aβ) plaques develop and lead to neurotoxicity in Alzheimer's disease remains a major challenge, particularly given the temporal delay and weak correlation between plaque deposition and cognitive decline. This study investigates how the evolving pathology of plaques affects the surrounding tissue, using a knock-in Aβ mouse model (App). We combined mass spectrometry imaging with stable isotope labeling to timestamp Aβ plaques from the moment of their initial deposition, enabling us to track their aging spatially. By integrating spatial transcriptomics, we linked changes in gene expression to the age of the plaques, independent of the mice's chronological age or disease stage. Here we show that older plaques were associated with reduced expression of synaptic genes. Additionally, when correlated with structure-specific dyes, we show that plaque age positively correlated with structural maturation. These more compact and older plaques were linked to greater synapse loss and increased toxicity.
了解淀粉样蛋白β（Aβ）斑块如何在阿尔茨海默病中形成并导致神经毒性仍然是一项重大挑战，特别是考虑到斑块沉积与认知衰退之间存在时间延迟且相关性较弱。本研究使用敲入Aβ小鼠模型（App），探究斑块不断演变的病理学如何影响周围组织。我们将质谱成像与稳定同位素标记相结合，从Aβ斑块初始沉积之时对其进行时间标记，从而能够在空间上追踪它们的老化过程。通过整合空间转录组学，我们将基因表达的变化与斑块的年龄联系起来，而不受小鼠实际年龄或疾病阶段的影响。在此我们表明，较老的斑块与突触基因表达降低有关。此外，当与结构特异性染料相关联时，我们发现斑块年龄与结构成熟呈正相关。这些更致密、更老的斑块与更大程度的突触丧失和毒性增加有关。
