Cathepsin B Deficiency Attenuates Tau Spreading via Modulation of Proteasome Activity in Neurons

The stereotypical propagation of pathological tau aggregates is a defining feature of Alzheimer's disease (AD) and related tauopathies. While interneuronal tau spreading drives clinical progression, the specific molecular pathways governing tau secretion and its subsequent proteostasis remain elusive.

We investigated the role of the cysteine protease Cathepsin B (CatB) using an adenoassociated virus (AAV)-mediated tau spreading mouse model. In parallel, an in vitro neuronal coculture system was employed to dissect the impact of CatB deficiency or pharmacological inhibition on tau secretion, uptake, lysosomal integrity, and proteasomal degradation.

CatB was significantly upregulated specifically in donor and recipient neurons during tau spreading, whereas it remained unchanged in microglia and astrocytes. Genetic deletion of CatB significantly reduced tau release from donor neurons without altering endocytic uptake in recipient neurons. Although CatB inhibition impaired lysosomal acidification, it paradoxically decreased tau propagation, potentially through a compensatory shift toward ubiquitin-proteasome systemmediated degradation, as observed in our in vitro models. This shift in the degradative axis effectively depleted the intracellular pool of tau available for secretion.

Our findings identify CatB as a critical neuronal regulator of the degradative balance governing tau spreading. We demonstrate that CatB deficiency limits tau propagation by shifting tau clearance toward the proteasome.

CatB is a strategic therapeutic target for mitigating tau-mediated neurotoxicity.