AI Article Synopsis
- Toxic amyloid beta (Aβ) species contribute to synaptic dysfunction and neurotoxicity in Alzheimer's disease (AD), with gamma-secretase being a crucial link to amyloid accumulation.
- A study identifies pyruvate kinase M2 (PKM2) as a positive regulator of gamma-secretase, primarily expressed in the brains of people with AD and animal models.
- PKM2 expression is induced by hypoxia, enhancing gamma-secretase activity, which in turn increases Aβ production and worsens memory deficits in AD model mice.
Article Abstract
Toxic amyloid beta (Aβ) species cause synaptic dysfunction and neurotoxicity in Alzheimer's disease (AD). As of yet, however, there are no reported regulators for gamma-secretase, which links a risky environment to amyloid accumulation in AD. Here, we report that pyruvate kinase M2 (PKM2) is a positive regulator of gamma-secretase under hypoxia. From a genome-wide functional screen, we identify PKM2 as a gamma-secretase activator that is highly expressed in the brains of both patients and murine models with AD. PKM2 regulates Aβ production and the amount of active gamma-secretase complex by changing the gene expression of aph-1 homolog. Hypoxia induces PKM2 expression, thereby promoting gamma-secretase activity. Moreover, transgenic expression of PKM2 in 3xTg AD model mice enhances hippocampal production of Aβ and exacerbates the impairment of spatial and recognition memory. Taken together, these findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aβ production and memory impairment under hypoxia.
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| http://dx.doi.org/10.1016/j.celrep.2021.110102 | DOI Listing |
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