Pathogenic Roles for Microtubule Stabilization Pathways in Alzheimers disease

Summary The two main neuropathological hallmarks associated with Alzheimer’s disease (AD) are amyloid beta plaques and intracellular neurofibrillary tangles comprised of hyperphosphorylated variants of the microtubule binding protein tau. These deposits lead to abnormal cellular structure and loss of synapses, both of which strongly affect behavior and memory. However, the pathogenic mechanisms that trigger the formation of these deposits and early synaptic dysfunction are still poorly understood and lack of this knowledge is a hurdle for the development of effective therapeutic strategies. Tubulin undergoes numerous post-translational modifications (PTMs) that affect both microtubule stability and associated proteins, including tau and microtubule-dependent motors. The tubulin de-tyrosination/tyrosination (deTyr/Tyr) cycle occurs when the C-terminal tyrosine of α-tubulin residing in a microtubule is episodically cleaved and then returned by a tubulin-tyrosine-ligase (TTL). Importantly, de- tyrosinated tubulin in neurons can be irreversibly converted by carboxypeptidases 1/6 to D2 tubulin by cleavage of the penultimate amino acid of glutamic acid. This change permanently removes D2 tubulin from the cycle. Loss of tubulin re-tyrosination and D2 tubulin accumulation are therefore hallmarks of microtubule longevity, although their effects on synaptic function and tau hyperphosphorylation are completely unknown. This proposal is designed to test the central hypothesis that inhibition of tubulin re-tyrosination and/or accumulation of D2 tubulin affect synaptic microtubule dynamics and induce tau hyperphosphorylation with severe consequences on neurotransmission. Our proposed studies are novel and highly significant, as they will examine a new role for dysregulation of the deTyr/Tyr tubulin cycle in promoting tau hyperphosphorylation and AD pathology in primary hippocampal neurons, mice and a human model of familial AD. The hypothesis relies on our preliminary data showing that: 1) defects in tubulin re-tyrosination correlate with AD progression and tau hyperphosphorylation in sporadic and familial AD; 2) loss of tubulin re- tyrosination promotes activation of the stress sensor and tau kinase AMPK, tau hyperphosphorylation and synaptic injury; 3) synaptic dynamic MTs play critical roles in synaptic and structural plasticity and changes in TTL expression can affect them. This proposal relies on a multidisciplinary effort to examine the in vitro and in vivo mechanisms by which premature tubulin longevity may drive tau hyperphosphorylation and AD-related synaptic dysfunction. The work has the potential to identify novel targets that may be modulated in drug therapies aimed at rescuing cognitive decline in sporadic and familial forms of AD.