Grant: Project Grant

Alzheimer's disease (AD) is a brain disease characterized by a gradual loss of memory, followed by deterioration of higher cognitive functions such as language, calculation and judgement. The pathological features associated with AD brain include the loss of nerve cells in selected regions along with abnormal deposits of certain molecules such as amyloid beta (Ab) peptide and tau protein in structures called plaques and tangles, respectively. The brain regions which are severely affected in AD are hippocampus and cortex, whereas certain other regions such as cerebellum and striatum are relatively spared. It is believed that accumulation of Ab peptide can trigger the loss of nerve cells, but why only selected cells die in AD brains remain unclear. There is evidence that leakage of lysosomal enzymes called cathepsins B and D from their storage sites is markedly increased in nerve cells before they die in AD brains, but the role of these enzymes in the death of these cells is not fully understood. In a series of experiments, we will first establish the significance of the leakage of cathepsins in Ab-induced death of nerve cells grown in Petri dishes and the underlying cause of leakage of these enzymes from their storage sites. In parallel, we will measure the levels and activity of these enzymes in affected as well as unaffected regions of genetically modified animal models of AD and in post-mortem human AD brain samples. Subsequently, we will determine whether nanoparticles that have been shown to restore leakage of cathepsins can protect nerve cells against Ab-mediated toxicity in Petri dishes and in animal models of AD. This study will establish the role of cathepsins in the selective loss of nerve cells in AD brains. Additionally, these results could lead to identification of new molecular targets for the early diagnosis and/or development of new therapeutic opportunities such as nanoparticles in preventing the loss of nerve cells in AD brains