Atrial Natriuretic Peptide Associated with Cardiovascular Diseases Inhibits Amyloid-β Aggregation via Cross-Seeding

Abstract

Both cardiovascular diseases (CVDs) and Alzheimer’s disease (AD) share some common risk factors (e.g., age, obesity, oxidative stress, inflammation, hypertension) that contribute to their overlapping pathogenesis, indicating a “head-to-heart” pathological connection between CVDs and AD. To explore this potential connection at the protein level, we study the potential cross-seeding (heterotypic interactions) between CVD-associated atrial natriuretic peptide (ANP) and AD-associated β-amyloid (Aβ). Collective aggregation and cell assays demonstrate the cross-seeding of ANP with different Aβ species including monomers, oligomers, and fibrils with high binding affinity (K D = 1.234–1.797 μM) in a dose-dependent manner. Such ANP-induced cross-seeding also modifies the Aβ aggregation pathway, fibril morphology, and cell deposition pattern by inhibiting Aβ fibrillization from small aggregates, disassembling preformed Aβ fibrils, and alleviating Aβ-associated cytotoxicity. Finally, using transgenic C. elegans worms that express the human muscle-specific Aβ1–42, ANP can also effectively delay Aβ-induced worm paralysis, decrease Aβ plaques in worm brains, and reduce reactive oxygen species (ROS) production, confirming its in vivo inhibition ability to prevent neurodevelopmental toxicity in worms. This work discovers not only a new cross-seeding system between the two disease-related proteins but also a new finding that ANP possesses a new biological function as an Aβ inhibitor in the nonaggregated state.

Repurposing Antimicrobial Protegrin-1 as a Dual-Function Amyloid Inhibitor via Cross-seeding

“…To capture the different stages of this process, specific timepoints were selected as the incubation time. This method has been widely utilized in numerous projects within our research group, ensuring the reliable characterization of Aβ aggregation dynamics. , Specifically, different aggregation stages, including Aβ seeds from 5 h of lag phase, 15 h of growth phase, 25 h of early equilibrium phase, and 36 h of later equilibrium phase, were selected. ThT kinetics curves in Figure a clearly show that the addition of PG-1 to different preformed Aβ seeds still produced strong inhibition effect on Aβ aggregation, as evidenced by the sudden drop of ThT signals at the time point of Aβ addition.…”

“…This method has been widely utilized in numerous projects within our research group, ensuring the reliable characterization of Aβ aggregation dynamics. 3,47 Specifically, different aggregation stages, including Aβ seeds from 5 h of lag phase, 15 h of growth phase, 25 h of early equilibrium phase, and 36 h of later equilibrium phase, were selected. ThT kinetics curves in Figure 2a S3).…”

Amyloid, Crohn’s disease, and Alzheimer’s disease - are they linked?

“…Aβ contributes in various disease and important pathways, and understanding these interactions may be helpful in the prevention and management of them. Atrial natriuretic peptide (ANP) through a process called ‘cross-seeding’ inhibits Aβ aggregation ( Tang et al., 2023 ). Gelsolin responsible for Finnish type of familial amyloidosis just like ANP inhibits the fibrilization of Aβ ( Maury, 1991 ; Ray et al., 2000 ).…”

Inhibition of Pancreatic Cancer Cells by Different Amyloid Proteins Reveals an Inverse Relationship between Neurodegenerative Diseases and Cancer

“…But, a growing body of epidemiologic studies suggest certain correlation between the risk of developing cancer and a neurodegenerative disorder, [ 1–4 ] probably because they share some common risk factors, including hypoxia, oxidative stress, and inflammation. [ 2,5,6 ] Particularly, aging, as the most obvious risk factor, is strongly correlated with both diseases, which have significant incidence rates at age 65 or above. Evidently, it is estimated that there will be ≈81.1 million people of age 65 and older suffering from neurodegenerative diseases by 2040, [ 7–10 ] while almost 14 million new cancer cases were predicted to be diagnosed in patients of >65‐year‐old by 2035 worldwide.…”