Current Alzheimer's disease (AD) therapies predominantly focus on amyloid-? (A?) peptides, but biomarker studies indicate that A? effects may be maximal before onset of clinical symptoms. Downstream of A?, synapse loss and intracellular accumulation of the microtubule-associated protein tau correlate strongly with cognitive decline, yet few therapeutic strategies target these mechanisms. Presently, twenty-nine kinase inhibitors are used to treat human diseases, and out of these, two are pan- Rho-associated protein kinases (ROCK) 1 and 2 inhibitors. In the mid-2000s, the ROCKs were identified as putative translational targets to curb A? production. However, progress on this exciting avenue languished due to three critical barriers: 1) the lack of connection between ROCKs and AD pathogenesis beyond mechanisms tied to A? generation, 2) the lack of genetic models to test the role of ROCK1 or ROCK2 in AD mice, and 3) the lack of kinase inhibitors offering high ROCK-selectivity and brain penetrance.
We aim to overcome these barriers with new data linking ROCKs to structural plasticity changes in AD progression and employing new ROCK1 and ROCK2 conditional knockout mice as well as novel pan- and isoform-selective ROCK inhibitors that exhibit high bioavailability and brain penetrance with no gross side-effects.
In Aim 1, we will address the contribution of ROCK1 and ROCK2 to A?-induced dendritic structure degeneration.
In Aim 2, we will test the effects of chronic ROCK inhibition in mouse models of AD, and in Aim 3, we will elucidate the mechanisms by which ROCK1 and ROCK2 mediate tau protein homeostasis and autophagy induction.
Tragically, the population of Americans suffering from Alzheimer's disease, the leading cause of dementia, is expected to grow unless new effective therapies are developed which target underlying disease-causing mechanisms. The Rho kinases influence critical aspects of Alzheimer's disease pathogenesis, including neuron connections, amyloid accumulation, and tau. Studying the Rho kinases will facilitate the development of drugs that target these enzymes for the treatment and prevention of Alzheimer's disease.
| Greathouse, Kelsey M; Boros, Benjamin D; Deslauriers, Josue F et al. (2018) Distinct and complementary functions of rho kinase isoforms ROCK1 and ROCK2 in prefrontal cortex structural plasticity. Brain Struct Funct 223:4227-4241 |
| Froula, Jessica M; Henderson, Benjamin W; Gonzalez, Jose Carlos et al. (2018) ?-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons. Acta Neuropathol Commun 6:35 |
| Boros, Benjamin D; Greathouse, Kelsey M; Gentry, Erik G et al. (2017) Dendritic spines provide cognitive resilience against Alzheimer's disease. Ann Neurol 82:602-614 |
