TTBK1 (tau tubulin kinase 1) is a neuron-specific serine/threonine kinase that belongs to the casein kinase superfamily and functions as a critical regulator of tau pathology 1. TTBK1 directly phosphorylates tau protein at multiple residues, particularly at Ser422, and also activates cycline-dependent kinase 5, thereby promoting tau aggregation and accumulation 1. Additionally, TTBK1 phosphorylates TDP-43, linking it to both tau and TDP-43-related proteinopathies 2. Mechanistically, TTBK1 drives neurodegeneration through tau hyperphosphorylation and by mediating pro-inflammatory M1-skewed microglial activation and axonal degeneration 1. TTBK1 protein expression is significantly elevated in Alzheimer's disease brains, and genetic variations in the TTBK1 gene are associated with late-onset Alzheimer's disease in multiple populations 1. TTBK1 transgenic mice crossed with tau mutants demonstrate progressive tau accumulation, neuroinflammation, and neurodegeneration 1. Clinical relevance extends to frontotemporal lobar degeneration, where elevated TTBK1/2 expression is observed in cortical and hippocampal neurons of FTLD patients 2. In vivo antisense oligonucleotide-based TTBK1 inhibition significantly reduces phosphorylated tau epitopes in PS19 tauopathy mice, supporting TTBK1 as a promising therapeutic target for neurodegenerative diseases 3.