Alzheimer's disease (AD) and Huntington's disease (HD) are neurological disorders where disease-specific proteins get misfolded causing aggregation and neuronal dysfunction. In AD, a small protein, amyloid £] peptide (A£]) considered as a culprit of the disease, is formed by proteolytic cleavages of transmembrane amyloid precursor protein with £] and £^ secretases. A£]ƒn is the major component of extracellular plaques and cerebrovascular amyloid deposits that are the hallmark of ADƒ\ƒn HD is a hereditary neurodegenerative disorder, which arises from the expansion of a long polyglutamine tract in the huntingtin (htt) gene product. Inhibition of A£] or mutant htt (mhtt) aggregation appears to be one of the therapeutic approaches to counteract AD and HD. However, formation of plaques and aggregates is most likely to happen later in the progression of the diseases, and targeting the early events in neurons that preclude aggregate formation and neuronal dysfunction could be more beneficial.Our recent data suggest that inhibition of axonal trafficking is an early event in the progression of both, AD and HD, and is detected in the neurons prior to the aggregate formation or the onset of any disease-related symptoms in mice. In particular, axonal trafficking of mitochondria is specifically inhibited in primary hippocampal and striatal neurons from mice representing AD and HD. Mitochondria moved slower in both, anterograde and retrograde directions and stopped more often in disease neurons. Altered trafficking was observed in embryonic neurons prior to the onset of neurological symptoms or mitochondrial dysfunction. Since dynamic mitochondrial network with actively moving mitochondria is essential for efficient calcium buffering, we tested the hypothesis that inability of mitochondria to move underlies calcium buffering defect observed in both, neurons from AD and HD mouse models. Indeed, when mitochondrial motility was inhibited with taxol in control neurons, we recapitulated calcium buffering defects observed in HD and AD. Thus, taxol treatment caused an excessive calcium increase during NMDA stimulation with consequent dose-dependent excitotoxic cell death. Our data suggest that axonal trafficking of mitochondria is an early dysfunction that is common to both, AD and HD, which eventually contributes to the altered calcium buffering and excitotoxic cell death in neurons.We have recently synthesized and tested various tricyclic pyrones (TP) and pyridinones compounds and demonstrated their ability to block A£] and mhtt aggregation in cell and animal models for the diseases. Moreover, TP compounds not only prevented aggregation in neurons but also reversed early cellular defects associated with HD. We propose to test whether treatment with TP compounds could restore axonal trafficking of mitochondria in AD neurons in vitro and AD mouse model in vivo, improve calcium homeostasis in response to glutamate treatment in hippocampal neurons and delay the onset of mitochondrial dysfunction in AD mice with age. Taken together, our experiments are designed to demonstrate in vitro and in vivo whether TP compounds could be used in neurodegenerative disorders not only to prevent late events in disease progression such as aggregation, but also whether these compounds could be used early to delay the onset of the symptoms and disease progression. Our investigation could reveal the molecular mechanism that involves axonal trafficking defects shared by many neurodegenerative disorders regardless of their cause. Data could pinpoint specific therapeutic approach applicable to many neurodegenerative disorders.