Dynamic changes in lysosome-related pathways in APP/PS1 mice with aging

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alzheimer's disease (AD) is characterized by amyloid β (Aβ) plaques, but the age-dependent mechanisms of Aβ toxicity and cognitive decline are unclear.
• Understanding these mechanisms is crucial for developing effective AD therapies.

Purpose of the Study:

• To investigate the age-dependent pathogenesis of AD and alterations in lysosomal pathways in the hippocampus of APP/PS1 mice.
• To elucidate the dynamic changes in cellular pathways contributing to neuronal and synaptic damage in aging AD models.

Main Methods:

• Transcriptome sequencing to identify differentially expressed genes.
• Molecular biology assays to analyze protein expression.
• Histopathological analyses (Nissl and Golgi staining) to assess neuronal and synaptic integrity.

Main Results:

• Early high expression of β-amyloid precursor protein (APP) and age-dependent Aβ deposition were observed.
• Transcriptome analysis revealed significant enrichment of lysosome-related genes.
• Lysosomal proteins (ATP6V0d2, CTSD), endosome function, autophagy, and the SGK1/FOXO3a pathway showed dynamic age-related changes.
• Neuronal loss and synaptic damage increased with age in the hippocampus.

Conclusions:

• The study defines age-gradient changes in the autophagy-lysosome and endosome/lysosome systems, and the SGK1/FOXO3a pathway in an AD mouse model.
• These findings offer insights into AD pathogenesis, particularly the transition from compensatory to decompensated states.
• The research highlights the importance of lysosomal function in age-dependent neurodegeneration in Alzheimer's disease.