Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond.

Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction. Observations from disease models, post-mortem histology, and clinical evidence have demonstrated that pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization, changes in solubility, mislocalization, and intercellular spreading. Despite extensive research, there are few disease-modifying or preventative therapeutics for AD and none for other tauopathies. Challenges faced in tauopathy drug development include an insufficient understanding of pathogenic mechanisms of tau proteoforms, limited specificity of agents tested, and inadequate levels of brain exposure, altogether underscoring the need for innovative therapeutic modalities. In recent years, the development of experimental therapeutic modalities, such as targeted protein degradation (TPD) strategies, has shown significant and promising potential to promote the degradation of disease-causing proteins, thereby reducing accumulation and aggregation. Here, we review all modalities of TPD that have been developed to target tau in the context of AD and FTD, as well as other approaches that with innovation could be adapted for tau-specific TPD.