Institute of Crystallography - CNR

The A?8-20 fragment as anti-fibrillogenic and neuroprotective agent: advancing towards efficient Alzheimer’s disease treatment

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by a spectrum of symptoms associated with memory loss and cognitive decline with deleterious consequences in everyday life. The lack of specific drugs for the treatment and/or prevention of this pathology makes AD an ever-increasing economic and social emergency. Oligomeric species of amyloid-beta (A?) are recognized as the primary cause responsible for synaptic dysfunction and neuronal degeneration, playing a crucial role in the onset of the pathology. Several studies have been focusing on the use of small molecules and peptides targeting oligomeric species to prevent A? aggregation and toxicity. Among them, peptide fragments derived from the primary sequence of A? have also been used to exploit any eventual recognition abilities toward the full-length A? parent peptide. Here, we test the A?8-20 fragment which contains the self-recognizing Lys-Leu-Val-Phe-Phe sequence and lacks Arg 5 and Asp 7 and the main part of the C-terminus, key points involved in the aggregation pathway and stabilization of the fibrillary structure of A?. In particular, by combining chemical and biological techniques, we show that A?8-20 does not undergo random coil to ? sheet conformational transition, does not form amyloid fibrils by itself, and is not toxic for neuronal cells. Moreover, we demonstrate that A?8-20 mainly interacts with the 4-11 region of A?1-42 and inhibits the formation of toxic oligomeric species and A? fibrils. Finally, our data show that A?8-20 protects neuron-like cells from A?1-42 oligomer toxicity. We propose A?8-20 as a promising drug candidate for the treatment of AD.

ACS chemical neuroscience
Impact factor
Stefania Zimbone, Maria Laura Giuffrida, Giuseppina Sabatino, Giuseppe Di Natale, Rita Tosto, Grazia M. L. Consoli, Danilo Milardi, Giuseppe Pappalardo, Michele F.M. Sciacca
not specified