DNLA Delayed the Appearance of Learning and Memory Impairment of APP/PS1 Mice: Involvement of mTOR/TFEB/v-ATPase Signaling Pathway.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with cognitive impairment that currently is incurable. There is existing evidence to suggest that vacuolar adenosine triphosphatase (v-ATPase) is one of the early key driving factors in the pathological process of AD. Thus, early intervention of v-ATPase may be a viable strategy.

Aims: Observing whether early intervention with DNLA can delay learning and memory impairment in mice, and further exploring the mechanism of DNLA delaying AD in vitro based on v-ATPase.

Methods: Four-month-old APP/PS1 transgenic mice were treated with alkaloids from Dendrobium nobile Lindl (DNLA) 20 and 40 mg/kg/day for 5 months. The Morris water maze test and nest test showed that DNLA administration significantly delayed the appearance of cognitive deficits in APP/PS1 mice. We further investigated the mechanism of DNLA promoting lysosome acidification in vitro by using PC12 cells.

Results: We found that DNLA increases the degradation of β-amyloid (Aβ) contained in the autophagic lysosomes and alleviates the aging of neurons by promoting lysosome acidification and improving autophagy flow. In PC12 cells, DDB could promote the separation of mTOR and lysosome, promote the nuclear translocation of transcription factor EB (TFEB), and then promote lysosome biogenesis and lysosome acidification by targeting ATP6V1A.

Conclusion: These results unraveled that preventive administration of DNLA may delay the impairment of learning and memory in APP/PS1 mice. The molecular mechanism may be related to promoting the mTOR-TFEB-v-ATPase pathway.