Label-Free Infrared Spectroscopic Imaging Reveals Heterogeneity of β‑Sheet Aggregates in Alzheimer’s Disease

• Published in: The journal of physical chemistry letters Vol. 12; no. 39; pp. 9662 - 9671
• Main Authors: Confer, Matthew P, Holcombe, Brooke M, Foes, Abigail G, Holmquist, John M, Walker, Savannah C, Deb, Sanghamitra, Ghosh, Ayanjeet
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07.10.2021
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - chemistry; Brain - metabolism; Humans; Physical Insights into the Biosphere, Atmosphere, and Space; Protein Aggregates; Protein Conformation, beta-Strand; Spectrophotometry, Infrared
• ISSN: 1948-7185; 1948-7185
• DOI: 10.1021/acs.jpclett.1c02306

The aggregation of the amyloid beta (Aβ) protein into plaques is a pathological feature of Alzheimer’s disease (AD). While amyloid aggregates have been extensively studied in vitro, their structural aspects and associated chemistry in the brain are not fully understood. In this report, we demonstrate, using infrared spectroscopic imaging, that Aβ plaques exhibit significant heterogeneities in terms of their secondary structure and phospholipid content. We show that the capabilities of discrete frequency infrared imaging (DFIR) are ideally suited for characterization of amyloid deposits in brain tissues and employ DFIR to identify nonplaque β-sheet aggregates distributed throughout brain tissues. We further demonstrate that phospholipid-rich β-sheet deposits exist outside of plaques in all diseased tissues, indicating their potential clinical significance. This is the very first application of DFIR toward a characterization of protein aggregates in an AD brain and provides a rapid, label-free approach that allows us to uncover β-sheet heterogeneities in the AD, which may be significant for targeted therapeutic strategies in the future.