Bcl-2-Homology-Only Proapoptotic Peptides Modulate beta-Amyloid Aggregation and Toxicity

: Aggregation of the fi-Amyloid (Afi) peptide in brain tissues is the hallmark of Alzheimer's disease (AD). While Afi is presumed to be insidiously involved in the disease's pathophysiology, concrete mechanisms accounting for the role of Afi in AD are yet to be deciphered. While Afi has been primarily identified in the extracellular space, the peptide also accumulates in cellular compartments such as mitochondria and lysosomes and impairs cellular functions. Here, we show that prominent proapoptotic peptides associated with the mitochondrial outer membrane, the Bcl-2-homology-only peptides BID, PUMA, and NOXA, exert significant and divergent effects upon aggregation, cytotoxicity, and membrane interactions of Afi42, the main Afi homolog. Interestingly, we show that BID and PUMA accelerated aggregation of Afi42, reduced Afi42-induced toxicity and mitochondrial disfunction, and inhibited Afi42-membrane interactions. In contrast, NOXA exhibited opposite effects, reducing Afi42 fibril formation, affecting more pronounced apoptotic effects and mitochondrial disfunction, and enhancing membrane interactions of Afi42. The effects of BID, PUMA, and NOXA upon the Afi42 structure and toxicity may be linked to its biological properties and affect pathophysiological features of AD.