Micromotor-enabled platform for early, minimally invasive monitoring of amyloid pathology along a putative plasma-brain-retina axis in a transgenic islet amyloid polypeptide mouse model.

Growing evidence indicates that metabolic dysfunction contributes to neurodegeneration, leading to the "type 3 diabetes" hypothesis. In this context, human islet amyloid polypeptide (hIAPP), a highly amyloidogenic peptide, has emerged as a potential molecular link between peripheral metabolic dysfunction and neurodegeneration. Here, we developed a hybrid ex vivo platform integrating micromotor (MMGO-AuNPs)-based electrochemical aptassay for the detection of circulating amyloid-β42 oligomers (AβO42) in human IAPP-overexpressing transgenic (Tg) and wild-type (Wt) mice, under high-fat diet (HFD). This design enabled longitudinal monitoring of circulating AβO42 together with the assessment of tissue amyloid deposition and associated alterations, providing preliminary evidence for a putative plasma-brain-retina axis. MMGO-AuNPs enabled rapid (5 min) and minimally invasive (5 μL) label-free electrochemical detection by SWV of circulating AβO42 in mice plasma. Longitudinal monitoring revealed increased plasma AβO42 at early stages, preceding cognitive and motor deficits. Plasma AβO42 levels were associated with hippocampal amyloid deposition and showed qualitative concordance with retinal amyloid-associated changes assessed by immunofluorescence (IF), as well as with behavioral and metabolic alterations exacerbated by HFD, demonstrating the sensitivity of this approach for early-stage AβO42 detection. Longitudinal analyses revealed heterogeneity in amylin accumulation, with some islets showing increased amylin deposition whereas others exhibited features consistent with β-cell senescence. These findings suggest a potential link between metabolic dysfunction and amyloid-associated neurodegeneration, consistent with the "type 3 diabetes" hypothesis. Overall, this integrated MM-based framework enables non-terminal longitudinal analysis and demonstrates the potential of active MM biosensing to quantify an early circulating AβO42 biomarker while linking it to tissue amyloid pathology and physiological outcomes, supporting the detection and monitoring of amyloid-associated neurodegeneration.