The pathogenesis of Alzheimer’s
disease (AD), the most prevalent
form of dementia, remains unclear. Over the past few years, evidence
has accumulated indicating that perturbed cerebral bioenergetics and
neuroinflammation may compromise cognitive functions and precedes
the onset of AD and that impaired function of glial cells can likely
contribute to the development of the disease. Recently, N6-methyladenosine
(m6A) modification of RNA has been implicated in the regulation of
different processes in the brain and to play a potential role in neurodegeneration.
In the present study, we investigated the potential role of the m6A
machinery enzymes in a streptozotocin (STZ) model of AD in human astrocytoma
CCF-STTG1 cells. We observed that STZ-treated astrocytes expressed
significantly higher levels of m6A demethylase fat mass and obesity-associated
protein (FTO) and m6A reader YTHDF1 (YTH domain-containing family
protein 1). Our experiments revealed that MO-I-500, a novel pharmacological
inhibitor of FTO, can strongly reduce the adverse effects of STZ.
Inhibition of FTO enhanced the survival of cells exposed to STZ and
suppressed oxidative stress, apoptosis, elevated expression of glial
fibrillary acidic protein, mitochondrial dysfunction, and bioenergetic
disturbances induced by this compound. Overall, the results of this
study indicate that perturbed m6A signaling may be contributing to
AD pathogenesis, likely by compromising astrocyte bioenergetics.
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