As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of toxic proteins called A?nd Tau, understanding the biological mechanisms by which A?onnects to tau dysfunction are critical for designing effective therapeutic treatments for AD. A?s generated from two cuts made by molecular scissors (named ?and ?-secretases) in its parent protein, APP, while Tau's main function is to stabilize microtubules. We found 4 major proteins (?integrin, RanBP9, Cofilin, & SSH1) in a pathway that not only promotes Aproduction but also relays the neurotoxic signals induced by A?o Tau, thereby promoting both pathologies. Inhibiting any one of these proteins could potentially stop the progression of AD, and as such, represent attractive and viable therapeutic targets. We have developed chemicals that inhibit one of these proteins (SSH1), the first ones ever characterized in academia or industry, and they show effectiveness not only in reducing A?roduction but also antagonizing A?nduced neurotoxicity and Tau dysfunction in nerve cells. By utilizing molecular, biochemical, cell biological, electrophysiological, and behavioral tools, we propose to 1) further characterize this pathway as intermediates between A?nd Tau pathologies in mouse models of Tau pathology and 2) better understand the physical and functional role of the RanBP9-SSH1-Cofilin pathway as critical nodes for bidirectional neurotoxic signaling between A?nd Tau pathologies in primary neurons, transfected cells, in the test tube, and in autopsied human brains.
The defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of A?nd Tau in brain associated with synapse loss, mitochondrial dysfunction, cytoskeletal aberrations, and cognitive decline. This application utilizes multiple integrated approaches in an effort to 1) understand and validate the molecular connections between A?nd Tau pathologies in mouse models of Tau pathology, and 2) precisely decipher the molecular connections between A?nd Tau in genetically modified primary neurons, transfected cell lines, in the test tube, and human autopsied brains. These studies are expected to shed novel insights to validating new therapeutic targets for AD.
| Woo, Jung-A A; Liu, Tian; Trotter, Courtney et al. (2017) Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. Nat Commun 8:15558 |
| Woo, Jung A; Liu, Tian; Zhao, Xingyu et al. (2017) Enhanced tau pathology via RanBP9 and Hsp90/Hsc70 chaperone complexes. Hum Mol Genet 26:3973-3988 |
| Liu, Tian; Wang, Fang; LePochat, Patrick et al. (2017) Cofilin-mediated Neuronal Apoptosis via p53 Translocation and PLD1 Regulation. Sci Rep 7:11532 |
