Non-Antibody Based Anti-Aggregation Therapies Targeting Amyloid-Beta, Tau and Alpha-Synuclein and Other Proteins Associated With Neurodegenerative Disorders

Dear Colleagues,

A substantial body of evidence indicates that the aggregation of specific proteins is a key component of most, if not all, chronic neurodegenerative disorders, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), corticobasal degeneration (CBD), cerebral amyloid angiopathy (CAA), chronic traumatic encephalitis (CTE),  and  Creutzfeldt–Jakob disease (CJD). Furthermore, and to make matters worse, a neurodegenerative disorder is usually associated with the aggregation of more than one protein. For example, the aggregation of Amyloid-beta peptide (Aβ), Tau protein, or Alpha-Synuclein (α-Syn) protein can be associated with PD, AD, FTLD, CBD, ALS, HD, and others (Moda et al., 2023). Interestingly, it also appears that several of the aggregating proteins associated with neurodegenerative disorders take on prion or prion-like properties, allowing for cell-to-cell propagation of the misfolded protein and, thereby, the spread of disease pathology within the CNS.

Current treatments targeting protein aggregation are limited and largely restricted to the application of antibodies, such as lecanemab and donanemab, to target Aβ aggregation. While anti-Aβ antibodies have demonstrated some recent success in slowing cognitive decline in early AD patients, this class of molecules has a number of limitations and challenges, such as the need for intravenous infusion every 2 to 4 weeks, providing only modest benefits and targeting one peptide/protein (e.g., Aβ). They are costly to produce and can be associated with the serious side effect of brain swelling.  Therefore, while an antibody approach provides proof-of-concept of targeting protein aggregation as a therapeutic option, its disadvantages highlight the need for small molecules and other agents, such as peptides, proteins, and antisense oligonucleotides, to target protein aggregation and its propagation associated with neurodegenerative disorders.

Therefore, this Special Issue aims to publish studies developing non-antibody-based therapeutics for Aβ and Tau, and α-Syn, as well as other proteins prone to aggregation, including but not limited to TAR DNA-binding protein 43 (TDP-43), superoxide dismutase (SOD1), Huntingtin (HTT), and prion protein (PrPᶜ).

Dr. Bruno Meloni
Guest Editor

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• amyloid-beta (Aβ) aggregation
• Tau aggregation
• alpha-synuclein (α-Syn) aggregation
• TAR DNA-binding protein 43 (TDP-43) aggregation
• superoxide dismutase (SOD1) aggregation
• Huntingtin (HTT) aggregation
• prion protein (PrPᶜ)
• protein aggregation
• anti-protein aggregating agents
• proteinopathies
• neurodegeneration