| First Author | Wang X | Year | 2024 |
| Journal | Alzheimers Res Ther | Volume | 16 |
| Issue | 1 | Pages | 121 |
| PubMed ID | 38831312 | Mgi Jnum | J:351190 |
| Mgi Id | MGI:7663057 | Doi | 10.1186/s13195-024-01489-6 |
| Citation | Wang X, et al. (2024) Intermittent hypoxia training enhances Abeta endocytosis by plaque associated microglia via VPS35-dependent TREM2 recycling in murine Alzheimer's disease. Alzheimers Res Ther 16(1):121 |
| abstractText | BACKGROUND: Beta-amyloid (Abeta) deposition in the brain parenchyma is a crucial initiating step in the amyloid cascade hypothesis of Alzheimer's disease (AD) pathology. Furthermore, dysfunction of plaque-associated microglia, also known as disease-associated microglia (DAM) has been reported to accelerate Abeta deposition and cognitive impairment. Our previous research demonstrated that intermittent hypoxia training (IHT) improved AD pathology by upregulating autophagy in DAM, thereby enhancing oligomeric Abeta (oAbeta) clearance. Considering that oAbeta internalization is the initial stage of oAbeta clearance, this study focused on the IHT mechanism involved in upregulating Abeta uptake by DAM. METHODS: IHT was administered to 8-month-old APP/PS1 mice or 6-month-old microglial vacuolar protein sorting 35 (VPS35) knockout mice in APP/PS1 background (MG VPS35 KO: APP/PS1) for 28 days. After the IHT, the spatial learning-memory capacity of the mice was assessed. Additionally, AD pathology was determined by estimating the nerve fiber and synapse density, Abeta plaque deposition, and Abeta load in the brain. A model of Abeta-exposed microglia was constructed and treated with IHT to explore the related mechanism. Finally, triggering receptor expressed on myeloid cells 2 (TREM2) intracellular recycling and Abeta internalization were measured using a fluorescence tracing technique. RESULTS: Our results showed that IHT ameliorated cognitive function and Abeta pathology. In particular, IHT enhanced Abeta endocytosis by augmenting the intracellular transport function of microglial TREM2, thereby contributing to Abeta clearance. Furthermore, IHT specifically upregulated VPS35 in DAM, the primary cause for the enhanced intracellular recycling of TREM2. IHT lost ameliorative effect on Abeta pathology in MG VPS35 KO: APP/PS1 mice brain. Lastly, the IHT mechanism of VPS35 upregulation in DAM was mediated by the transcriptional regulation of VPS35 by transcription factor EB (TFEB). CONCLUSION: IHT enhances Abeta endocytosis in DAM by upregulating VPS35-dependent TREM2 recycling, thereby facilitating oAbeta clearance and mitigation of Abeta pathology. Moreover, the transcriptional regulation of VPS35 by TFEB demonstrates a close link between endocytosis and autophagy in microglia. Our study further elucidates the IHT mechanism in improving AD pathology and provides evidence supporting the potential application of IHT as a complementary therapy for AD. |
