Unique secretory lysosomal tau species are linked to dementia rate in Alzheimer's patients

We demonstrate that cognitively resilient AD patients, characterized by reduced tau pathology, maintain lysosomal integrity, whereas cognitively vulnerable AD patients, exhibiting greater tau pathology, display compromised lysosomes. Lysosomes in cognitively vulnerable AD brains contain partially digested, seed-competent pathogenic tau proteins. These proteins primarily consist of the amyloidogenic core, with peripheral regions degraded. The partially digested tau species are secreted, facilitating the spread of tau pathology and contributing to severe cognitive decline. We have demonstrated that tau aggregates can be secreted extracellularly via lysosomal exocytosis, which may facilitate the spread of tau pathology across different brain region CONCLUSION: In conclusion, this study underscores the pivotal role of lysosomal integrity in modulating tau pathology and cognitive outcomes in AD. Dysfunctional lysosomes, marked by altered protein expression, pH dysregulation, and tau accumulation, can drive tau propagation and severe cognitive decline. Targeting lysosomal exocytosis pathways offers a promising avenue for mitigating tau pathology and promoting cognitive resilience in Alzheimer's diseases.