Synaptic proteins that aggregate and degrade slower with aging accumulate in microglia

Area of Science:

• Neuroscience
• Molecular Biology
• Aging Research

Background:

• Neurodegenerative diseases are a global health challenge, characterized by protein aggregation and loss of neuronal protein maintenance.
• Aging is a primary risk factor for neurodegeneration, yet the molecular mechanisms remain incompletely understood.

Purpose of the Study:

• To investigate age-related changes in neuronal proteome turnover and aggregation using novel bioorthogonal tools.
• To identify proteins accumulating in microglia and their relationship to neuronal aging and neurodegeneration.

Main Methods:

• Engineered bioorthogonal tools to tag and track the nascent neuronal proteome in aging mice.
• Analyzed protein turnover rates, aggregation propensity, and protein accumulation in microglia across different ages and brain regions.

Main Results:

• Neuronal proteins degraded twice as slowly in aged (24-month) versus young (4-month) mice, with regional variations in protein stability.
• Identified an 'aggregome' of 574 aged neuronal proteins, with 30% showing reduced degradation; many were previously unlinked to neurodegeneration.
• Discovered 274 neuronal proteins accumulating in microglia, 65% of which showed age-related degradation defects or aggregation; synaptic proteins were notably enriched.

Conclusions:

• Aging causes a significant decline in neuronal proteome maintenance, contributing to protein aggregation and neurodegeneration.
• Impaired synaptic protein turnover and aggregation may trigger microglial responses, potentially leading to synapse engulfment.
• These findings offer insights into age-related cognitive decline and identify novel therapeutic targets for neurodegenerative diseases.