Unravelling ApoE4 contribution to tau-mediated synaptic degeneration in AD by combining advanced proteomics and super resolution microscopy

Introduction

Alzheimer’s disease (AD) is one of the biggest scientific and socio-economic challenges of the 21st century. Currently, there is no cure. Aggregates of amyloid-β and tau protein, along with neuroinflammation/gliosis, are hallmarks of AD that lead to synaptic and neuronal loss as the basis for cognitive decline. The latter correlates closely with the brain distribution of tau aggregates, providing a strong incentive to investigate a link between tau accumulation and synaptic degeneration.

Role of ApoE

Brain apolipoprotein E (ApoE), mainly produced by astrocytes, is essential for lipid transport to neurons and synaptic functions. The ApoE4 isoform is the strongest genetic risk factor for AD and contributes to tau-mediated neurodegeneration. Determining how ApoE4 controls tau-mediated synaptic degeneration is thus essential to understand AD and develop efficient treatments. This requires fine characterization of ApoE4 functions at tau-damaged synapses with synaptic resolution.

Research Hypothesis

SynApoE will test in 3 work packages the hypothesis that ApoE4 worsens tau-mediated synaptic degeneration by altering the astrocyte/neuron interactions at the synapse:

1. SYNAPTIC CHANGES: Identify directly at tau-damaged synapses the ApoE4-mediated structural and functional synaptic changes.
2. PROTEIN PLAYERS: Identify the protein players underlying these structural and functional synaptic changes.
3. MECHANISMS: Discover the mechanisms through which ApoE4 promotes tau-associated synaptic degeneration, based on the protein players identified in WP2.

Objectives

SynApoE aims to decipher how ApoE4 drives tau-mediated synaptic degeneration, providing a deeper understanding of AD pathophysiology.

Methodology

SynApoE achieves unprecedented synaptic resolution by combining:

• Advanced proteomics
• Super resolution microscopy at synapses
• Electrophysiology
• Behavioral testing

This will help unravel the mechanisms leading to synaptic loss and subsequent cognitive decline, providing new targets for drug design to protect synapses.