Therapeutic evaluation of targeting Tau Tubulin kinase-1 in Alzheimer’s disease

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Alzheimer’s disease (AD) is the most common form of senile dementia without effective treatments after countless number of clinical trials for over decades. This application proposes in vitro and in vivo evaluation of targeting human tau-tubulin kinase (TTBK1), a neuron specific tau kinase involved in the phosphorylation and aggregation of microtubule-associated protein tau in human and mice and genetically associated with late- onset AD in Spanish and Chinese cohorts. TTBK1 protein expression was significantly increased in the frontal cortex of postmortem AD brains compared to the control subject, suggesting that TTBK1 may play critical roles in AD pathogenesis. Our recent neuropathological examination of postmortem brain tissues revealed abundant expression of TTBK1 in the entorhinal cortex (EC) layer II and CA1 region of the hippocampal field where early tau pathology evolves in AD. Importantly, several studies reported that CA1 neuronal loss was correlated with cognitive decline in AD, and that CA1 connectivity to medial temporal cortex was associated with reduced episodic memory with mild cognitive impairment patients as determined by functional MRI. Interestingly, we found that TTBK1 significantly reduced axonal integrity of EC pyramidal neurons in AD mouse model, mimicking the early AD pathology. Thus, suppressing initial pathological tau accumulation in the EC and their spread to CA1 region by targeting TTBK1 could halt progression of AD at the prodromal stage. There are several attempts to develop TTBK1 kinase inhibitors, which were unsuccessful due to their cross-reactivity with TTBK2, a ubiquitous tau-tubulin kinase involved in mitosis and ciliogenesis. In this proposal, we will test the therapeutic specificity and efficiency of antisense oligonucleotides (ASOs) targeting TTBK1, which have little cross-reactivity to TTBK2. The central hypothesis of our proposal is that ASO-TTBK1 reduces accumulation and spread of pathological tau in early-stage AD brains. Our exciting preliminary data have shown that ASO- TTBK1 significantly reduced the level of phosphorylated tau at pSer396, pThr231 and pThr181 in the hippocampal region in PS19 tau mice. We will examine the therapeutic effect of ASO-TTBK1 on tau pathology and cognitive function in PS19 mice and our recently developed early tau propagation model (ECII-CA1 tau mice, Aim 1). We will further validate the effect of ASO-TTBK1 on tau pathology in human induced pluripotent stem cell-derived neurons and organoids isolated from late onset AD and FTDP-17 (P301L MAPT) cases in vitro (Aim 2) and on human TTBK1 transgenic and TTBK1:APP knock-in double transgenic mice in vivo (Aim 3). Successful completion of these experiments will validate TTBK1 as a therapeutic target of tauopathy and ASO as a translatable approach for targeting TTBK1 in AD brains.