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A VEGF Fragment Encompassing Residues 10-30 Inhibits Aβ1-42 Amyloid Aggregation and Exhibits Neuroprotective
Stefania Zimbone1, M Laura Giuffrida1, Michele F M Sciacca1
1Consiglio Nazionale delle Ricerche, Istituto di Cristallografia, Catania 95126, Italy.
ACS Chemical Neuroscience
|November 26, 2024
Summary
A novel peptide fragment of vascular endothelial growth factor (VEGF) effectively inhibits amyloid-beta (Aβ) aggregation, a key factor in Alzheimer's disease (AD). This peptide also protects against Aβ-induced neurotoxicity, offering a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Brain vascular diseases and neurodegeneration share common molecular mechanisms, with increasing incidence due to aging populations.
- Amyloid-beta (Aβ) peptide aggregation is linked to cerebral amyloid angiopathy (CAA), while elevated cerebrospinal fluid (CSF) vascular endothelial growth factor (VEGF) correlates with slower cognitive decline in Alzheimer's disease (AD).
Purpose of the Study:
- To investigate the potential of a specific VEGF peptide fragment (Pep9, residues 10-30) in inhibiting Aβ aggregation and preventing Aβ-induced neurotoxicity.
- To explore the therapeutic implications of VEGF fragments in Alzheimer's disease treatment.
Main Methods:
- Synthesis and testing of a VEGF-derived peptide (Pep9) for its ability to inhibit Aβ1-42 aggregation.
- Atomic Force Microscopy (AFM) to analyze peptide-induced conformational changes in Aβ.
- Cell-based assays using differentiated neuroblastoma SH-SY5Y cells to evaluate Pep9's neuroprotective effects against Aβ toxicity.
- Utilizing a control peptide (H11G/H12G) to confirm the sequence-specific activity of Pep9.
Main Results:
- Pep9 significantly inhibited the aggregation of Aβ1-42 peptides and the formation of toxic oligomers.
- AFM studies confirmed Pep9's anti-aggregation capacity and its role in reducing the random coil to beta-sheet transition in Aβ.
- Pep9 demonstrated potent neuroprotective effects, preventing amyloid-induced neuronal death in SH-SY5Y cells, outperforming full-length VEGF.
- A control peptide with mutated histidines lost significant anti-aggregating and neuroprotective activity, highlighting the importance of the peptide's amino acid sequence.
Conclusions:
- Specific fragments of VEGF, such as Pep9, possess significant anti-amyloidogenic and neuroprotective properties relevant to Alzheimer's disease.
- VEGF fragments represent a promising therapeutic avenue for treating Alzheimer's disease by targeting Aβ pathology.
- The study elucidates a novel role for VEGF in modulating Aβ aggregation and offers insights into potential treatments for neurodegenerative conditions.
