Significance Of Cytosolic Cathepsin D In Alzheimer'S Disease Pathology: Protective Cellular Effects Of Plga Nanoparticles Against Beta-Amyloid-Toxicity

Background: Evidence suggests that amyloid beta (A beta) peptides play an important role in the degeneration of neurons during the development of Alzheimer's disease (AD), the prevalent cause of dementia affecting the elderly. The endosomal-lysosomal system, which acts as a major site for A beta metabolism, has been shown to exhibit abnormalities in vulnerable neurons of the AD brain, reflected by enhanced levels/expression of lysosomal enzymes including cathepsin D (CatD). At present, the implication of CatD in selective neuronal vulnerability in AD pathology remains unclear. Methods We evaluated the role of CatD in the degeneration of neurons in A beta-treated cultures, transgenic AD mouse model (that is 5xFAD) andpost mortemAD brain samples. Results Our results showed that A beta(1-42)-induced toxicity in cortical cultured neurons is associated with impaired lysosomal integrity, enhanced levels of carbonylated proteins and tau phosphorylation. The cellular and cytosolic levels/activity of CatD are also elevated in cultured neurons following exposure to A beta peptide. Additionally, we observed that CatD cellular and subcellular levels/activity are increased in the affected cortex, but not in the unaffected cerebellum, of 5xFAD mice andpost mortemAD brains. Interestingly, treatment of cultured neurons with nanoparticles PLGA, which targets lysosomal system, attenuated A beta toxicity by reducing the levels of carbonylated proteins, tau phosphorylation and the level/distribution/activity of CatD. Conclusion Our study reveals that increased cytosolic level/activity of CatD play an important role in determining neuronal vulnerability in AD. Additionally, native PLGA can protect neurons against A beta toxicity by restoring lysosomal membrane integrity, thus signifying its implication in attenuating AD.