BACKGROUND:
Alzheimer’s disease (AD) is characterized by progressive accumulation of β-amyloid and MAPT/tau pathology, which spreads across brain regions in a prion-like manner. However, AD patients at similar neuropathological Braak stage VI can show very different levels of cognitive decline, suggesting underlying protective or risk mechanisms. Lysosomes, central to protein degradation, also participate in tau secretion via exocytosis. This study investigated whether lysosomal integrity influences cognitive resilience or vulnerability in AD patients.
METHODS:
Frozen postmortem prefrontal cortex tissues (Brodmann area 10) were obtained from cognitively normal individuals and Braak stage VI AD cases, stratified as cognitively resilient (CDR-2) or vulnerable (CDR-5). Lysosomes were isolated using density gradient centrifugation. Protein expression of lysosomal markers (LAMP1, ATP6V1A) and autophagy proteins was analyzed by western blotting and immunohistochemistry. Tau seeding and degradation assays were performed in HEK293 and tau FRET biosensor cells. Lysosomal pH was probed using LysoSensor dye, and tau fibril structure was visualized by transmission electron microscopy (TEM). Live-cell imaging and TIRF microscopy monitored lysosome-mediated tau exocytosis.
RESULTS:
Cognitively resilient AD brains maintained lysosomal integrity, while vulnerable cases displayed increased LAMP1 expression, reduced ATP6V1A:LAMP1 ratios, and elevated lysosomal pH, indicating dysfunction. Lysosomes from vulnerable AD brains accumulated partially digested tau fibrils retaining the amyloidogenic core but lacking peripheral regions. These core fibrils resisted degradation, retained seeding capacity, and induced synaptic loss in neuronal cultures. TEM confirmed the presence of paired helical filaments inside lysosomes. Lysosome-mediated tau secretion was upregulated in vulnerable cases, with live imaging showing tau release from LAMP1-positive vesicles. Inhibition of lysosomal exocytosis with vacuolin-1 reduced extracellular tau. Notably, female AD patients in the vulnerable group exhibited higher levels of lysosomal tau secretion compared to males.
CONCLUSION:
This study identifies lysosomal dysfunction as a key determinant of cognitive vulnerability in AD, where impaired degradation allows accumulation of seed-competent tau fibrils that are secreted via lysosomal exocytosis. These findings explain heterogeneity in dementia progression and highlight therapeutic avenues: restoring lysosomal integrity, inhibiting lysosomal exocytosis, and targeting the amyloidogenic tau core may mitigate propagation and promote cognitive resilience in AD.