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

Alzheimers disease (AD) is one of the biggest scientific and socio-economic challenges of the 21st century. Currently, there is no cure.

Aggregates of amyloid- 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.Brain apolipoprotein E (ApoE), mainly produced by astrocytes, is essential for lipid transport to neurons and synaptic functions.

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, yet this requires fine characterization of ApoE4 functions at tau-damaged synapses with a synaptic resolution.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.SynApoE aims to decipher how ApoE4 drives tau-mediated synaptic degeneration, providing a deeper understanding of AD pathophysiology.

SynApoE achieves unprecedented synaptic resolution by combining advanced proteomics, super resolution microscopy at synapses, electrophysiology and 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.