Digging Deep into Alzheimer Disease: How Electron Microscopy Helps Elucidating Its Pathogenesis

Area of Science:

• Neuroscience
• Pathology
• Biophysics

Background:

• Alzheimer disease (AD) is a progressive neurodegenerative disorder with no cure.
• Understanding subcellular alterations is key to elucidating AD mechanisms and developing treatments.
• Electron microscopy (EM) has historically been vital in characterizing AD pathology.

Purpose of the Study:

• To review the state of knowledge on EM-based studies in Alzheimer disease.
• To emphasize the central role of EM in advancing mechanistic understanding and translational approaches for AD.
• To highlight how EM reveals subcellular alterations critical for AD pathogenesis.

Main Methods:

• Review of conventional transmission and scanning EM studies.
• Integration of advanced EM techniques: volume EM (vEM), cryo-electron microscopy (cryo-EM), and cryo-electron tomography (cryo-ET).
• Analysis of EM data from human tissues, animal models, cell cultures, and synthetic assemblies.

Main Results:

• EM has characterized key AD ultrastructures like amyloid-beta (Aβ) deposits and paired helical filaments (PHFs).
• Advanced EM techniques provide near-native, near-atomic resolution 3D reconstructions of AD pathology.
• EM has identified the contribution of various subcellular compartments (synapses, mitochondria, lysosomes, etc.) to AD pathogenesis.

Conclusions:

• EM is an indispensable tool for dissecting AD disease mechanisms at the subcellular level.
• EM provides a comprehensive view of the AD subcellular landscape, essential for therapeutic development.
• EM studies facilitate cross-system comparisons, highlighting conserved pathological features and guiding rational drug design.