Targeting amyloid proteins for clinical diagnosis of neurodegenerative diseases

Abstract

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.

Keywords: Alzheimer's disease; Amyloid aggregation; Biomarker; Clinical diagnosis; Neurodegenerative diseases; Positron emission tomography (PET) tracer; Post-translational modification; Tau.

Fig. 1

Schematic diagram of PET imaging for pathological amyloid aggregates in the brain of patients and identifying biomarkers based on PTM profile of pathological amyloid proteins in the CSF and plasma of patients.

Fig. 2

PET imaging for Aβ and Tau amyloid aggregation in the human brain. (a) A brief introduction of PET imaging technology. PET imaging is initiated by injection of a small amount of radioactive tracer into the patient's peripheral veins. Radiotracers accumulate in the tissues by binding to their targets, and emit positrons (anti-electrons). The positron collides with a free electron and an annihilation reaction occurs, resulting in two gamma rays (photons) with energies of 511 keV released into opposite directions, which can be detected by a PET scanner surrounding the patient's brain. Three-dimensional images, reconstructed from the recorded projection data by mathematical algorithms, show the distribution of the positron-emitting molecules in the brain. (b) Biomarker trajectories in AD.

Fig. 3

Development and structural characterization of PET tracers for Aβ and Tau fibrils. (a) Timeline of the development of PET tracers. (b) Binding pattern of FMM with Aβ40 fibrils determined by ssNMR, reproduced from Duan et al. (2022) with permission from ACS Publications. (c) Binding pattern of DDNP with Tau fibrils (VQIVYK) determined by X-ray micro-crystallography, reproduced from Landau et al. (2011) with permission from PLOS Biology. (d) Binding pattern of APN1607 with Tau fibrils (PHFs and SFs) determined by cryo-EM, reproduced from Shi et al. (2021) with permission from Springer Nature.

Fig. 4

PTMs characterization and its application in Tau PTM study during AD progression. (a) Protein PTM characterization and biomarker discovery workflow by using MS. (b) Schematic illustration of the sequential accumulation of different PTMs of Tau at different disease stages. Increased phosphorylation in the proline-rich region (PRR) is followed by acetylation and ubiquitination in the microtubule-binding domain (MBD) during disease progression, reproduced from Wesseling et al. (2020) with permission from Elsevier.

Fig. 5

PTMs of different amyloid proteins and their roles in conformational selection for Tau filaments. (a) Sites of the identified PTMs by MS on three different amyloid proteins with the chemical structures of the different PTMs highlighted. (b) The structural model of how different PTMs determine Tau filament structures, reproduced from Arakhamia et al. (2020) with permission from Elsevier.