Ollonen, T., Kurkela, M., Laitakari, A. et al. Activation of the hypoxia response protects mice from amyloid-β accumulation. Cell. Mol. Life Sci. 79, 432 (2022). https://doi.org/10.1007/s00018-022-04460-6
Activation of the hypoxia response protects mice from amyloid-β accumulation
|Author:||Ollonen, Teemu1; Kurkela, Margareta1; Laitakari, Anna1;|
1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Aapistie 7C, P.O. Box 5400, 90014, Oulu, Finland
2A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
|Online Access:||PDF Full Text (PDF, 5.8 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022122072883
|Publish Date:|| 2022-12-20
Alzheimer’s disease (AD) is the most common cause of dementia with limited treatment options affecting millions of people and the prevalence increasing with the aging population. The current knowledge on the role of the hypoxia/hypoxia-inducible factor (HIF) in the AD pathology is restricted and controversial. We hypothesized based on benefits of the genetic long-term inactivation of HIF prolyl 4-hydroxylase-2 (HIF-P4H-2) on metabolism, vasculature and inflammatory response that prolonged moderate activation of the hypoxia response could hinder AD pathology. We used an aging model to study potential spontaneous accumulation of amyloid-β (Aβ) in HIF-P4H-2-deficient mice and a transgenic APP/PSEN1 mouse model subjected to prolonged sustained environmental hypoxia (15% O2 for 6 weeks) at two different time points of the disease; at age of 4 and 10 months. In both settings, activation of the hypoxia response reduced brain protein aggregate levels and this associated with higher vascularity. In the senescent HIF-P4H-2-deficient mice metabolic reprogramming also contributed to less protein aggregates while in APP/PSEN1 mice lesser Aβ associated additionally with hypoxia-mediated favorable responses to neuroinflammation and amyloid precursor protein processing. In conclusion, continuous, non-full-scale activation of the HIF pathway appears to mediate protection against neurodegeneration via several mechanisms and should be studied as a treatment option for AD.
Cellular and molecular life sciences
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
Open Access funding provided by University of Oulu including Oulu University Hospital. This work was supported by Academy of Finland grants 266719 and 308009 (PK), and 296498 (JMy), the Academy of Finland Center of Excellence 2012–2017 grants 251314 and 284605 (JMy), and grants from the S. Jusélius Foundation (PK and JMy) and the Jane and Aatos Erkko Foundation (PK and JMy) and Biocenter Finland.
|Academy of Finland Grant Number:||
251314 (Academy of Finland Funding decision)
284605 (Academy of Finland Funding decision)
266719 (Academy of Finland Funding decision)
308009 (Academy of Finland Funding decision)
296498 (Academy of Finland Funding decision)
All data are provided in the paper and supplementary information. The online version contains supplementary material available at https://doi.org/10.1007/s00018-022-04460-6.
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