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

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.