Heptamer Peptide Disassembles Native Amyloid in Human Plasma Through Heat Shock Protein 70

Area of Science:

• Biochemistry
• Neuroscience
• Molecular Biology

Background:

• Proteostasis, crucial for cellular health, relies on heat shock proteins (HSPs) to manage misfolded proteins.
• Failure in proteostasis leads to protein aggregate accumulation, a hallmark of neurodegenerative diseases and aging.
• Existing therapies often struggle with systemic delivery and targeting endogenous repair mechanisms.

Purpose of the Study:

• To investigate the effect of the neuroprotective peptide CHEC-7 on protein aggregates in human plasma.
• To determine if CHEC-7 can inhibit amyloidogenesis, specifically amyloid-beta (Aβ) aggregates.
• To elucidate the role of heat shock protein 70 (HSP70) in CHEC-7's mechanism of action.

Main Methods:

• Addition of CHEC-7 to human plasma containing amyloid-beta (Aβ1-40, 1-42) aggregates.
• Assessment of aggregate disruption and amyloidogenesis inhibition.
• Inhibition of endogenous HSP70 activity using antibody blocking and pifithrin-μ.

Main Results:

• CHEC-7 effectively disrupted protein aggregates, including Aβ, at nanomolar concentrations in human plasma.
• The peptide's activity was dependent on the presence and function of endogenous HSP70.
• Antibody blocking and HSP70 inhibition abolished CHEC-7's disaggregase effects.

Conclusions:

• CHEC-7 is the first high-affinity compound identified to stimulate HSP70's disaggregase activity systemically.
• This peptide activates an endogenous protein repair mechanism, offering a novel therapeutic strategy.
• CHEC-7 holds promise for treating protein aggregate diseases, including age-related protein repair failures and neurodegeneration.