Wood Jack I, Dulewicz Maciej, Ge Junyue, Stringer Katie, Szadziewska Alicja, Desai Sneha, Koutarapu Srinivas, Hajar Haady B, Fenson Lydia, Blennow Kaj, Zetterberg Henrik, Cummings Damian M, Savas Jeffrey N, Edwards Frances A, Hanrieder Jörg
Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, House V, S-431 80 Mölndal, Sweden.
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom.
Res Sq. 2025 Jan 22:rs.3.rs-5829037. doi: 10.21203/rs.3.rs-5829037/v1.
Understanding how amyloid beta (Aβ) plaques form and progress to neurotoxicity in Alzheimer's disease remains a significant challenge. This study aims to elucidate the processes involved in Aβ plaque formation and maturation using a knock-in Aβ mouse model ( ). By employing mass spectrometry imaging and stable isotope labeling, we timestamped Aβ plaques from their initial deposition, enabling the spatial tracking of plaque aging. Correlating single-plaque spatial transcriptomics with time since seeding, allowed us to track gene-expression changes specifically associated with plaque age, independent of chronological age of the mouse or disease severity. We found that plaque age, within sections from individual mice aged from 10 to 18 months, negatively correlates with synaptic gene expression. Further, correlation with hyperspectral confocal microscopy using structure-specific dyes revealed a positive link between plaque age and structural maturity, with older plaques identified as more compact and associated with significantly greater synapse loss and toxicity.
了解淀粉样β（Aβ）斑块如何在阿尔茨海默病中形成并发展为神经毒性仍然是一项重大挑战。本研究旨在利用敲入Aβ小鼠模型阐明Aβ斑块形成和成熟过程。通过采用质谱成像和稳定同位素标记，我们对Aβ斑块从最初沉积开始进行了时间标记，从而能够对斑块老化进行空间追踪。将单斑块空间转录组学与接种后的时间相关联，使我们能够追踪与斑块年龄特异性相关的基因表达变化，而不受小鼠实际年龄或疾病严重程度的影响。我们发现，在10至18个月龄的个体小鼠切片中，斑块年龄与突触基因表达呈负相关。此外，使用结构特异性染料与高光谱共聚焦显微镜的相关性揭示了斑块年龄与结构成熟度之间的正相关，较老的斑块被确定为更致密，并且与明显更多的突触丧失和毒性相关。
