Aβ Aggregate-Gated Ratiometric Probe Reveals Peri-Plaque Acidification Arising from Lysosomal Dysfunction in Alzheimer’s Disease

Abstract Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaques surrounded by plaque-associated dystrophic neurites (PADNs), where dysfunctional autolysosomal vesicles accumulate abundantly. However, whether Aβ-induced autolysosomal dysfunction contributes to remodeling of the plaque microenvironment remains unclear. Herein, we developed DQ, an Aβ aggregate-gated ratiometric fluorescent probe in which recognition of fibrillar Aβ activates pH-responsive fluorescence. This target-triggered sensing strategy restricts pH reporting to the vicinity of Aβ aggregates, enabling selective visualization of local plaque-associated microenvironments with minimal background interference. DQ exhibited high selectivity toward fibrillar Aβ and enabled imaging of local pH changes in both cellular models and transgenic AD mice. Using DQ, we revealed progressive acidification surrounding plaques during AD progression and demonstrated an age-dependent increase in peri-plaque acidification. Furthermore, imaging analyses showed that local acidification was closely associated with lysosomal dysfunction within PADNs. Mechanistic studies further demonstrated that autolysosomal impairment within PADNs causes lysosomal proton leakage and microenvironmental acidification. Repair of lysosomal dysfunction alleviated multiple AD-associated pathological features, including plaque burden, neuroinflammation, synaptic loss, and cognitive impairment. Collectively, this work establishes a target-gated ratiometric sensing strategy for spatially resolved interrogation of plaque-associated microenvironments and identifies PADN-associated lysosomal proton dysregulation as an important pathological event in AD progression.