Mapping Alzheimer's Molecular Pathologies in Large-Scale Connectomics Data: A Publicly Accessible Correlative...

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) and hyperphosphorylated-Tau (pTau) pathologies.
• Connectomics, using volume-electron-microscopy, maps neuronal networks to understand circuit function and dysfunction.
• Understanding the interplay between AD pathologies and neural circuits is crucial for developing effective treatments.

Purpose of the Study:

• To develop and present a volumetric-correlated-light-and-electron microscopy (vCLEM) protocol for localizing Aβ and pTau within large-scale connectomics datasets.
• To create a publicly accessible vCLEM dataset from the hippocampus of a 3xTg AD mouse model.
• To investigate the ultrastructural context of Aβ and pTau in relation to neurons, glia, and synapses.

Main Methods:

• Utilized fluorescent nanobodies for Aβ and pTau localization.
• Applied vCLEM to a large-scale connectomics dataset from the 3xTg AD mouse model hippocampus.
• Segmented neurons, glia, and synapses within the ultrastructural context.

Main Results:

• Generated a publicly accessible vCLEM dataset with localized Aβ and pTau at the ultrastructural level.
• Identified novel localizations of pTau, including spine-like protrusions at the axon initial segment.
• Observed alterations in synapse number and size in proximity to Aβ plaques.

Conclusions:

• The vCLEM approach effectively integrates molecular pathology with large-scale connectomics.
• This method facilitates the discovery of molecular and structural changes in neurodegenerative diseases like AD.
• The generated dataset serves as a valuable resource for advancing connectomics research in neurodegenerative diseases.