Therapeutic Strategies for Alzheimer's Disease Targeting Tau Protein and Microtubule Axis

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex course, and at present, only symptom management is available. Given that microtubule disassembly and neuronal toxicity caused by Tau hyperphosphorylation and aggregation are central to the onset and progression of AD, targeting the "Tau-microtubule axis" has become one of the main directions for the development of disease-modifying therapies (DMTs). This article systematically reviews the latest progress in intervention strategies targeting the Tau-microtubule axis according to the logical framework of "Tau pathogenic mechanisms—targeting Tau expression—inhibiting Tau aggregation—stabilizing microtubule structure—modulating EB1/EB3 dynamics and restoring their downstream repair programs". First, soluble oligomers (TauO) resulting from abnormal phosphorylation of the Tau protein can cause microtubule destabilization, synaptic toxicity and pathological spread, and exhibit synergistic toxicity with Aβ. Second, mRNA-level degradation (e.g., ASO drugs such as BIIB080 and AAV-miRNA) and immunotherapies can reduce pathological Tau expression at the source or peripherally; small-molecule inhibitors (e.g., LMTX and ACI-3024) can block the formation of toxic Tau aggregates. Third, microtubule stabilizers (e.g., Epothilone D, NAP) can restore the axonal transport network, and allosteric inhibitors (e.g., EBIN) can correct pathological calcium overload in the endoplasmic reticulum by blocking the abnormal binding of EB3 to IP3R3 and activate chromatin remodeling and repair programs. Single-target strategies have the problems of low blood-brain barrier permeability and limited intracellular target access. The following developments are expected to include high-precision biomarker screening (e.g., p-tau217, Tau-PET), new delivery vehicles, and combination therapies that target multiple links in the Tau-microtubule axis.