Spatial Single-Cell Proteomics Reveals Molecular Trajectories Of Tangle-Bearing Neurons In Alzheimer's Disease

Area of Science:

• Neuroscience
• Proteomics
• Pathology

Background:

• Neurofibrillary tangles of hyperphosphorylated tau are key in Alzheimer's disease (AD).
• The transition from normal tau to tangle pathology is not well understood.

Purpose of the Study:

• To investigate the proteomic changes in individual neurons during Alzheimer's disease progression.
• To understand the continuum of neuronal states and adaptive responses in tau pathogenesis.

Main Methods:

• Integrated laser microdissection of human AD brain tissue with mass spectrometry-based proteomics.
• Analyzed proteomes of individual tangle-positive and tangle-negative neurons.
• Utilized pseudotime analysis and AI for proteomic data interpretation.

Main Results:

• Identified thousands of proteins and tau phosphorylation sites directly from brain tissue.
• Revealed a continuum of proteomic changes in neurons correlating with tau abundance, not discrete classes.
• Early stages show altered proteostasis and lysosomal pathways, followed by synaptic disruption.
• Neurons with tangles showed molecular adaptation rather than acute cell death.

Conclusions:

• Established a framework for single-cell proteome analysis in human brain disease.
• Defined a continuum of neuronal states in tau pathogenesis, highlighting early vulnerabilities and adaptations in AD.