Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model

Rongcan Luo; Ling-Yan Su; Guiyu Li; Jing Yang; Qianjin Liu; Lu-Xiu Yang; Deng-Feng Zhang; Hejiang Zhou; Min Xu; Yu Fan; Jiali Li; Yong-Gang Yao

doi:10.1080/15548627.2019.1596488

Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model

Autophagy. 2020 Jan;16(1):52-69. doi: 10.1080/15548627.2019.1596488. Epub 2019 Apr 6.

Authors

Rongcan Luo^{1

2}, Ling-Yan Su^{1

3}, Guiyu Li^{1

2}, Jing Yang^{1

2}, Qianjin Liu^{1

2}, Lu-Xiu Yang¹, Deng-Feng Zhang^{1

3}, Hejiang Zhou¹, Min Xu^{1

2}, Yu Fan¹, Jiali Li¹, Yong-Gang Yao^{1

2

4

5}

Affiliations

¹ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
² Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, China.
³ Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, China.
⁴ CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
⁵ KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.

Abstract

Alzheimer disease (AD) is the most common neurodegenerative disease. An imbalance between the production and clearance of Aβ (amyloid beta) is considered to be actively involved in AD pathogenesis. Macroautophagy/autophagy is a major cellular pathway leading to the removal of aggregated proteins, and upregulation of autophagy represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. PPARA/PPARα (peroxisome proliferator activated receptor alpha) is a transcription factor that regulates genes involved in fatty acid metabolism and activates hepatic autophagy. We hypothesized that PPARA regulates autophagy in the nervous system and PPARA-mediated autophagy affects AD. We found that pharmacological activation of PPARA by the PPARA agonists gemfibrozil and Wy14643 induces autophagy in human microglia (HM) cells and U251 human glioma cells stably expressing the human APP (amyloid beta precursor protein) mutant (APP-p.M671L) and this effect is PPARA-dependent. Administration of PPARA agonists decreases amyloid pathology and reverses memory deficits and anxiety symptoms in APP-PSEN1ΔE9 mice. There is a reduced level of soluble Aβ and insoluble Aβ in hippocampus and cortex tissues from APP-PSEN1ΔE9 mice after treatment with either gemfibrozil or Wy14643, which promoted the recruitment of microglia and astrocytes to the vicinity of Aβ plaques and enhanced autophagosome biogenesis. These results indicated that PPARA is an important factor regulating autophagy in the clearance of Aβ and suggested gemfibrozil be assessed as a possible treatment for AD.Abbreviation: Aβ: amyloid beta; ACTB: actin beta; ADAM10: ADAM metallopeptidase domain 10; AD: Alzheimer disease; AIF1/IBA1: allograft inflammatory factor 1; ANOVA: analysis of variance; APOE: apolipoprotein E; APP: amyloid beta precursor protein; APP-PSEN1ΔE9: APPswe/PSEN1dE9; BAFA1: bafilomycin A₁; BDNF: brain derived neurotrophic factor; BECN1: beclin 1; CD68: CD68 molecule; CREB1: cAMP responsive element binding protein 1; DAPI: 4',6-diamidino-2-phenylindole; DLG4/PSD-95: discs large MAGUK scaffold protein 4; DMSO: dimethyl sulfoxide; ELISA: enzyme linked immunosorbent assay; FDA: U.S. Food and Drug Administration; FKBP5: FK506 binding protein 5; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; gemfibrozil: 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid; GFAP: glial fibrillary acidic protein; GLI2/THP1: GLI family zinc finger 2; HM: human microglia; IL6: interleukin 6; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NC: negative control; OQ: opposite quadrant; PPARA/PPARα, peroxisome proliferator activated receptor alpha; PSEN1/PS1: presenilin 1; SEM: standard error of the mean; SQSTM1: sequestosome 1; SYP: synaptophysin; TFEB: transcription factor EB; TNF/TNF-α: tumor necrosis factor; TQ: target quadrant; WT: wild type; Wy14643: 2-[4-chloro-6-(2,3-dimethylanilino)pyrimidin-2-yl]sulfanylacetic acid.

Keywords: Alzheimer disease; Aβ; PPARA; Wy14643; autophagy; gemfibrozil.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism
Alzheimer Disease / pathology*
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / metabolism
Animals
Autophagy / genetics
Autophagy / physiology*
Cognitive Dysfunction / metabolism
Disease Models, Animal
Humans
Mice
Microglia / metabolism
Neurodegenerative Diseases / metabolism
PPAR alpha / genetics
PPAR alpha / metabolism*
Plaque, Amyloid / metabolism

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
PPAR alpha
PPARA protein, human
Ppara protein, mouse

Grants and funding

The study was done at Kunming Institute of Zoology, Chinese Academy of Sciences (CAS), and was supported by the National Natural Science Foundation of China (31730037 to YGY and 31601039 to DFZ), the Strategic Priority Research Program (B) of CAS (XDB32020200 to YGY), the Project for International Collaboration of the Bureau of International Collaboration, CAS (GJHZ1846 to YGY), and the Bureau of Frontier Sciences and Education, CAS (grant no. QYZDJ-SSW-SMC005 to YGY).