O4‐01‐02: Structure‐based Inhibitors of Amyloid‐ Beta Core Suggest a Common Interface With Tau
Year: 2019
Type: article
Abstract: Alzheimer's disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau, but the molecular linkage of Aβ to tau remains unresolved. One proposed disease mechanism is through cross-seeding events, in which a compatible interface on aggregated Aβ induces tau to misfold. A crystal structure of the Aβ core (Aβ16-25D23N) determined by electron diffraction displaying characteristics of both fibrillar and oligomeric structure was used to design inhibitors. These inhibitors were validated for efficacy by testing for reduced aggregation and toxicity of monomeric Aβ, as well as toxicity of pre-formed Aβ aggregates in model N2a cells. Aβ fibrils treated with inhibitors reduced cross-seeding events in tau HEK293 biosensor cells. The inhibitors also reduced aggregation and homotypic seeding of tau. Mutations of amyloidogenic regions of tau were probed to identify key interfaces affected by our peptide inhibitor. Fibrils extracted from autopsied brains of patients with Alzheimer's disease were tested with the inhibitors for seeding in tau HEK293 biosensor cells to verify that these inhibitors target disease related conformations. Inhibitors targeting the Aβ core effectively block aggregation and toxicity of Aβ1-42, as well as reduced the seeded spread of tau aggregation from recombinant Aβ or tau fibrils, and AD derived fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests that these aggregates share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline. Targeting this epitope could prove an effective strategy for targeting disease spread.
Source: Alzheimer s & Dementia
Institution: University of California, Los Angeles
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2990025083