Generic beta-sheet-rich protein aggregates

Generic beta-sheet-rich protein aggregates, commonly referred to as amyloid fibrils, are insoluble protein polymers characterized by a highly ordered cross-beta sheet quaternary structure [1]. These structures form when normally soluble proteins or peptides undergo a conformational change and self-assemble into stable, filamentous deposits [2]. This process is a central pathological feature in over 50 human diseases, including Alzheimer's disease, Parkinson's disease, and various forms of systemic amyloidosis [3]. While the primary amino acid sequence of the constituent proteins varies, the shared beta-sheet architecture allows for the development of diagnostic tracers and therapeutic antibodies that recognize the aggregate fold rather than a specific sequence [4]. Current therapeutic strategies include the use of monoclonal antibodies to promote the clearance of these aggregates from the brain and small molecules designed to inhibit fibril elongation or promote disaggregation [5]. Diagnostic agents, such as thioflavin derivatives, specifically bind to the grooves of the beta-sheet structure, enabling the clinical assessment of amyloid plaque density in vivo [6]. References: [1] Sipe JD, et al. Amyloid. 2016;23(4):209-213. [2] Chiti F, Dobson CM. Annu Rev Biochem. 2017;86:27-68. [3] Benson MD, et al. Amyloid. 2018;25(4):215-219. [4] Sevigny J, et al. Nature. 2016;537(7618):50-56. [5] Panza F, et al. Nat Rev Neurol. 2019;15(2):73-88. [6] Vallabhajosula S. Semn Nucl Med. 2011;41(4):283-299.

Other names

Amyloid fibrilsCross-beta aggregatesMisfolded protein aggregatesAmyloid-like depositsProteinaceous aggregates

Therapeutic agents targeting these aggregates typically function by inhibiting the assembly of monomers into fibrils, promoting the disaggregation of existing deposits, or facilitating the clearance of aggregates via microglial phagocytosis. Diagnostic agents utilize the repetitive, cross-beta sheet structure to bind with high affinity, allowing for the visualization of amyloid burden through medical imaging techniques like PET.