Other
12 Authors
- Diwan A,
- Gonzales E,
- Liu H,
- Yan P,
- Lee JM,
- Zhu A,
- Perez R,
- Ma X,
- Xiao Q,
- Schuler DR,
- Cirrito JR,
- Burchett JM
| First Author | Xiao Q | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 29 | Pages | 9607-20 |
| PubMed ID | 25031402 | Mgi Jnum | J:348875 |
| Mgi Id | MGI:7645571 | Doi | 10.1523/JNEUROSCI.3788-13.2014 |
| Citation | Xiao Q, et al. (2014) Enhancing astrocytic lysosome biogenesis facilitates Abeta clearance and attenuates amyloid plaque pathogenesis. J Neurosci 34(29):9607-20 |
| abstractText | In sporadic Alzheimer's disease (AD), impaired Abeta removal contributes to elevated extracellular Abeta levels that drive amyloid plaque pathogenesis. Extracellular proteolysis, export across the blood-brain barrier, and cellular uptake facilitate physiologic Abeta clearance. Astrocytes can take up and degrade Abeta, but it remains unclear whether this function is insufficient in AD or can be enhanced to accelerate Abeta removal. Additionally, age-related dysfunction of lysosomes, the major degradative organelles wherein Abeta localizes after uptake, has been implicated in amyloid plaque pathogenesis. We tested the hypothesis that enhancing lysosomal function in astrocytes with transcription factor EB (TFEB), a master regulator of lysosome biogenesis, would promote Abeta uptake and catabolism and attenuate plaque pathogenesis. Exogenous TFEB localized to the nucleus with transcriptional induction of lysosomal biogenesis and function in vitro. This resulted in significantly accelerated uptake of exogenously applied Abeta42, with increased localization to and degradation within lysosomes in C17.2 cells and primary astrocytes, indicating that TFEB is sufficient to coordinately enhance uptake, trafficking, and degradation of Abeta. Stereotactic injection of adeno-associated viral particles carrying TFEB driven by a glial fibrillary acidic protein promoter was used to achieve astrocyte-specific expression in the hippocampus of APP/PS1 transgenic mice. Exogenous TFEB localized to astrocyte nuclei and enhanced lysosome function, resulting in reduced Abeta levels and shortened half-life in the brain interstitial fluid and reduced amyloid plaque load in the hippocampus compared with control virus-injected mice. Therefore, activation of TFEB in astrocytes is an effective strategy to restore adequate Abeta removal and counter amyloid plaque pathogenesis in AD. |
