Basic Science and Pathogenesis

BACKGROUND: Diabetes has been regarded as an independent risk factor for Alzheimer's disease(AD). This study investigates the effect of diabetes on autophagosome-lysosome fusion using STZ-induced diabetic rats and SH-SY5Y cells, aiming to clarify the molecular mechanisms linking diabetes to Aβ deposition and AD pathogenesis. METHOD: In vivo, STZ-induced diabetic rats were tested using the Open-field and Morris water maze tests to assess cognitive function. Hippocampal ultrastructural changes were observed via electron microscopy, while Western blot and qRT-PCR were used to measure Aβ, CTSD, CTSL, and Rab7 expression. In vitro, SH-SY5Y cells were cultured under high glucose (HG) conditions with or without rapamycin (Rap) or 3MA. Autophagy was analyzed using electron microscopy and mRFP-GFP-LC3 adenovirus transfection. Lysosomal activity (ACP2) was measured via ELISA, and apoptosis was assessed using flow cytometry. RESULT: Diabetic rats showed impaired spatial memory in the Morris water maze test and increased hippocampal Aβ expression, with decreased CTSD and CTSL levels. SH-SY5Y cells in the HG group exhibited increased autophagosomes and enhanced autophagic flux but reduced lysosomal ACP2 activity. Rab7, Cath L, and Cath D levels were lower in the HG group, impairing autophagosome-lysosome fusion and Aβ clearance. Rapamycin improved lysosomal function, reduced apoptosis, and restored Rab7, Cath L, and Cath D levels, while 3MA exacerbated these impairments. CONCLUSION: Diabetes disrupts autophagosome-lysosome fusion, impairing Aβ clearance and lysosomal function, leading to increased apoptosis and cognitive dysfunction. These findings provide insights into the mechanisms of diabetes-related AD and suggest potential therapeutic targets.