| First Author | Wang X | Year | 2023 |
| Journal | J Neuroinflammation | Volume | 20 |
| Issue | 1 | Pages | 240 |
| PubMed ID | 37864249 | Mgi Jnum | J:342061 |
| Mgi Id | MGI:7544478 | Doi | 10.1186/s12974-023-02931-6 |
| Citation | Wang X, et al. (2023) Intermittent hypoxia therapy ameliorates beta-amyloid pathology via TFEB-mediated autophagy in murine Alzheimer's disease. J Neuroinflammation 20(1):240 |
| abstractText | BACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Impaired autophagy in plaque-associated microglia (PAM) has been reported to accelerate amyloid plaque deposition and cognitive impairment in AD pathogenesis. Recent evidence suggests that the transcription factor EB (TFEB)-mediated activation of the autophagy-lysosomal pathway is a promising treatment approach for AD. Moreover, the complementary therapy of intermittent hypoxia therapy (IHT) has been shown to upregulate autophagy and impart beneficial effects in patients with AD. However, the effect of IHT on PAM remains unknown. METHODS: 8-Month-old APP/PS1 mice were treated with IHT for 28 days. Spatial learning memory capacity and anxiety in mice were investigated. AD pathology was determined by the quantity of nerve fibers and synapses density, numbers of microglia and neurons, Abeta plaque deposition, pro-inflammatory factors, and the content of Abeta in the brain. TFEB-mediated autophagy was determined by western blot and qRT-PCR. Primary microglia were treated with oligomeric Abeta 1-42 (oAbeta) combined with IHT for mechanism exploration. Differential genes were screened by RNA-seq. Autophagic degradation process of intracellular oAbeta was traced by immunofluorescence. RESULTS: In this study, we found that IHT ameliorated cognitive function by attenuating neuronal loss and axonal injury in an AD animal model (APP/PS1 mice) with beta-amyloid (Abeta) pathology. In addition, IHT-mediated neuronal protection was associated with reduced Abeta accumulation and plaque formation. Using an in vitro PAM model, we further confirmed that IHT upregulated autophagy-related proteins, thereby promoting the Abeta autophagic degradation by PAM. Mechanistically, IHT facilitated the nuclear localization of TFEB in PAM, with TFEB activity showing a positive correlation with Abeta degradation by PAM in vivo and in vitro. In addition, IHT-induced TFEB activation was associated with the inhibition of the AKT-MAPK-mTOR pathway. CONCLUSIONS: These results suggest that IHT alleviates neuronal damage and neuroinflammation via the upregulation of TFEB-dependent Abeta clearance by PAM, leading to improved learning and memory in AD mice. Therefore, IHT may be a promising non-pharmacologic therapy in complementary medicine against AD. |
