Formaldehyde‐Crosslinked Nontoxic Aβ Monomers to Form Toxic Aβ Dimers and Aggregates: Pathogenicity and Therapeutic Perspectives. (8th September 2021)

• Record Type: Journal Article
• Authors: Zhao, Hang; Huang, Xuerong; Tong, Zhiqian
• Is Part Of: ChemMedChem. Volume 16:Number 22(2021)
• Page Start: 3376
• Page End: 3390
• Publication Date: 2021-09-08
• Subjects: Aβ monomer -- Aβ dimer -- blood-brain barrier (BBB) -- extracellular space (ECS) -- formaldehyde (FA); Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100428
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Alzheimer's disease (AD) is characterized by the presence of senile plaques in the brain. However, medicines targeting amyloid‐beta (Aβ) have not achieved the expected clinical effects. This review focuses on the formation mechanism of the Aβ dimer (the basic unit of oligomers and fibrils) and its tremendous potential as a drug target. Recently, age‐associated formaldehyde and Aβ‐derived formaldehyde have been found to crosslink the nontoxic Aβ monomer to form the toxic dimers, oligomers and fibrils. Particularly, Aβ‐induced formaldehyde accumulation and formaldehyde‐promoted Aβ aggregation form a vicious cycle. Subsequently, formaldehyde initiates Aβ toxicity in both the early‐and late‐onset AD. These facts also explain why AD drugs targeting only Aβ do not have the desired therapeutic effects. Development of the nanoparticle‐based medicines targeting both formaldehyde and Aβ dimer is a promising strategy for improving the drug efficacy by penetrating blood‐brain barrier and extracellular space into the cortical neurons in AD patients. Abstract : Age‐related formaldehyde (FA) metabolism disorders lead to the accumulation of FA. In Alzheimer's disease (AD), β‐amyloid (Aβ) binding formaldehyde dehydrogenase (FDH) induces its inactivation and FA overload. FA‐crosslinked nontoxic Aβ monomers form toxic Aβ dimers, and Aβ‐promoted FA generation and FA‐elicited Aβ assembly create a vicious cycle. Nanodrugs that target both FA and Aβ dimers are thus a new strategy for AD treatment.