Targeting amyloid proteins for clinical diagnosis of neurodegenerative diseases

Abnormal aggregation and accumulation of pathological amyloid proteins such as amyloid-β, Tau, and α-synuclein play key pathological roles and serve as histological hallmarks in different neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). In addition, various post-translational modifications (PTMs) have been identified on pathological amyloid proteins and are subjected to change during disease progression. Given the central role of amyloid proteins in NDs, tremendous efforts have been made to develop amyloid-targeting strategies for clinical diagnosis and molecular classification of NDs. In this review, we summarize two major strategies for targeting amyloid aggregates, with a focus on the trials in AD diagnosis. The first strategy is a positron emission tomography (PET) scan of protein aggregation in the brain. We mainly focus on introducing the development of small-molecule PET tracers for specifically recognizing pathological amyloid fibrils. The second strategy is the detection of PTM biomarkers on amyloid proteins in cerebrospinal fluid and plasma. We discuss the pathological roles of different PTMs in diseases and how we can use the PTM profile of amyloid proteins for clinical diagnosis. Finally, we point out the potential technical challenges of these two strategies, and outline other potential strategies, as well as a combination of multiple strategies, for molecular diagnosis of NDs.