# Deep Profiling of the Aging Proteome Depicts Neuroinflammation, Synaptic Function, and Phosphorylation in an Accelerated Alzheimer's Disease Cell Model

## TL;DR

This study uses advanced proteomics to analyze an accelerated Alzheimer's model, revealing age-related changes in proteins linked to inflammation, synapses, and phosphorylation.

## Contribution

The study introduces an accelerated AD model combining aging and AD mutations, revealing novel proteomic and phosphoproteomic features.

## Key findings

- The acAD model showed broader proteome remodeling, including synaptic and cytoskeletal changes and increased inflammation.
- Phosphorylation patterns in acAD aligned with those observed in two murine AD models.
- Over 6000 proteins were quantified, showing pathway-level changes in neuronal signaling and mitochondrial dynamics.

## Abstract

Alzheimer's disease (AD) is an age-associated neurodegenerative disorder characterized by amyloid plaques, tau hyperphosphorylation, and synaptic dysfunction. Most available cellular AD models lack aging features, limiting their ability to recapitulate key pathological mechanisms. Here we applied high-resolution mass spectrometry-based multiplexed proteomics and phosphoproteomics in a discovery setting to characterize an accelerated AD (acAD) model that combines amyloid precursor protein (APP) and presenilin (PSEN) mutations with progerin, an aging-associated Lamin A mutant that accelerates aging. Across four phenotypes (control, progerin, classic AD, and acAD), we identified 8279 proteins, quantified 6081 proteins, and detected phosphorylation dynamics. Relative to the classic model, acAD exhibited broader proteome remodeling, including amplified downregulation of synaptic and cytoskeletal proteins, upregulation of transcription and translation machinery, and pathway-level changes in neuronal signaling, mitochondrial dynamics, and neuroinflammation. Phosphoproteome analysis revealed widespread changes in RNA-binding and cytoskeletal proteins, aligning with recent data from two murine AD models. These findings show that acAD captures canonical AD phenotypes while uniquely modeling age-related inflammation and phosphorylation, providing a resource to accelerate studies of proteome-level mechanisms of AD progression and to inform strategies targeting cytoskeletal and inflammatory pathways.

•High-resolution proteomics quantified >6000 proteins among four aging cell models.•The acAD model amplified synaptic loss, translation machinery, and inflammation.•Phosphorylation patterns in acAD aligned with murine AD systems.

High-resolution proteomics quantified >6000 proteins among four aging cell models.

The acAD model amplified synaptic loss, translation machinery, and inflammation.

Phosphorylation patterns in acAD aligned with murine AD systems.

We applied HRMS-based multiplexed proteomics to characterize an accelerated Alzheimer’s disease cell model, uncovering amplified synaptic and cytoskeletal remodeling and phosphoproteomic shifts that mirror murine AD models.