Title : Impaired tau-secretory lysosomes are linked to cognitive vulnerability in Alzheimer patients
Abstract:
Tau proteins propagate between brain regions in a prion-like manner, driving the progression of Alzheimer disease (AD). Although tau pathology strongly correlates with cognitive decline, substantial heterogeneity exists among patients with comparable neuropathological burden, suggesting mechanisms underlying cognitive resilience and vulnerability. Emerging evidence implicates lysosomal dysfunction in tau accumulation and secretion; however, its contribution to cognitive heterogeneity in AD remains poorly understood.
In this study, postmortem prefrontal cortex tissues from neuropathologically confirmed cognitively resilient and cognitively vulnerable AD individuals with Braak stage VI were analyzed to investigate lysosome-associated tau pathology. Lysosomes were isolated and characterized using biochemical assays, immunoblotting, immunohistochemistry, electron microscopy, live-cell imaging, and tau biosensor assays to evaluate lysosomal integrity, tau degradation, and secretion dynamics.
Cognitively vulnerable AD cases exhibited pronounced lysosomal dysfunction characterized by enlarged lysosomes, altered acidification, impaired V-ATPase regulation, and accumulation of partially degraded tau fibrils within lysosomal compartments. These lysosome-associated tau species retained strong seeding competence and promoted synaptic toxicity in neuronal cultures. In contrast, cognitively resilient individuals demonstrated preserved lysosomal homeostasis and reduced lysosomal tau accumulation despite similar pathological burden. Furthermore, lysosomal exocytosis was markedly elevated in cognitively vulnerable cases, facilitating extracellular release and propagation of pathogenic tau species. Sex-specific differences were also observed, with female patients exhibiting increased lysosomal tau burden and secretion.
Collectively, these findings identify impaired lysosomal pathways as key determinants of cognitive vulnerability in Alzheimer disease. Preservation of lysosomal integrity may contribute to cognitive resilience despite advanced tau pathology. These results highlight lysosome-mediated tau processing and secretion as promising therapeutic targets for limiting tau propagation and slowing disease progression in AD.
