Aggregation of the β-Amyloid (Aβ) peptide in brain tissues is the hallmark of Alzheimer's disease (AD). While Aβ is presumed to be insidiously involved in the disease's pathophysiology, concrete mechanisms accounting for the role of Aβ in AD are yet to be deciphered. While Aβ 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 Aβ42, the main Aβ homolog. Interestingly, we show that BID and PUMA accelerated aggregation of Aβ42, reduced Aβ42-induced toxicity and mitochondrial disfunction, and inhibited Aβ42-membrane interactions. In contrast, NOXA exhibited opposite effects, reducing Aβ42 fibril formation, affecting more pronounced apoptotic effects and mitochondrial disfunction, and enhancing membrane interactions of Aβ42. The effects of BID, PUMA, and NOXA upon the Aβ42 structure and toxicity may be linked to its biological properties and affect pathophysiological features of AD.
Keywords: Alzheimer’s disease (AD); Bcl-2 homology 3 (BH3) peptides; amyloid β (Aβ); apoptosis; mitochondrial membranes.