Peptide-loaded chitosan nanoparticles improve mitochondrial and cognitive functions via inhibition of Aβ-ABAD interaction in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is the most prevalent form of dementia. Mitochondrial dysfunction is recognized among the earliest pathological events in AD, and is closely-linked with the accumulation of amyloid-beta (Aβ) plaques which is a well-established hallmark of AD. The interplay between the two converges on the interaction of Aβ with the mitochondrial enzyme Aβ-binding alcohol dehydrogenase (ABAD), and the formation of Aβ-ABAD complex. This leads to the suppression of the normal function of ABAD, and elicits a number of detrimental events such as the excessive generation of reactive oxygen species (ROS) resulting in apoptosis of neuronal cells. To intercept the Aβ-ABAD interaction, a decoy peptide (DP) was employed, and was loaded into polymeric chitosan nanoparticles (CSNPs) for efficient delivery across the blood–brain barrier (BBB). In vivo studies on control and neuroinflammatory mouse models confirmed that NPs of the smaller size (SNPs; 59 ± 6 nm) accumulated in the brain with minimal off-target delivery. Unlike free DP, DP-loaded SNPs significantly improved cognitive functions as depicted by the modified Y-maze test. The DP also had protective effects on the mitochondria that were associated with a decrease in Aβ, an increase in ATP and a normalization in SOD activity. Additionally, the restoration of ABAD normal function was reflected by elevated estradiol levels. These findings indicate that the inhibition of Aβ-ABAD complex ameliorates Aβ-induced toxicity in AD, consequently enhancing both mitochondrial and cognitive functions.