Monitoring Acidification Preceding Aβ Deposition in Alzheimer's Disease

Abstract Amyloid beta (Aβ) is the primary early biomarker of Alzheimer's disease (AD), and since an acidic environment promotes Aβ aggregation, acidification plays a crucial role in AD progression. In this study, a novel acid‐responsive near‐infrared (NIR) fluorescent probe alongside multiple molecular biology techniques to investigate the temporal relationship between acidification and Aβ deposition, as well as the underlying mechanisms of acidification is employed. By monitoring 2‐ to 11‐month‐old APP/PS1 mice and wild‐type (WT) mice, it is detected significant fluorescence signal in APP/PS1 mice beginning at 3 months preceding Aβ deposition at 5 months, and peaking at 5 months, followed by cognitive deficits at 8 months. Additionally, elevated monocarboxylate transporter 4 (MCT4) protein expression in 3‐month‐old APP/PS1 mice indicated disruption of astrocyte‐neuron lactate shuttle (ANLS) homeostasis. Overall, this findings first demonstrate that acidification precedes Aβ deposition, peaks at the onset of Aβ deposition, and diminishes thereafter, with early acidification likely driven by the disruption of ANLS.