Background: Emerging evidence supports the hypothesis that metabolism dysfunction is involved
in pathogenesis of Alzheimer’s disease (AD). One aspect of metabolic dysfunction includes dysregulation
of adenosine monophosphate kinase protein kinase (AMPK) and mammalian target of rapamycin
(mTOR) metabolic axis, which is extensively present in some of the leading causes of AD such
as cerebrovascular diseases, type 2 diabetes and brain ischaemic events. While the molecular basis underlying
this metabolic dysregulation remains a significant challenge, mitochondrial dysfunction due to
aging appears to be an essential factor to activate AMPK/mTOR signaling pathway, leading to abnormal
neuronal energy metabolism and AD pathology.
Methods: Using immunofluorescent imaging by Lecia confocal microscopy, we analyzed the activation
of AMPK/mTOR. Concurrently, the level of mitochondrial antioxidant enzymes of superoxide
dismutase 2 (SOD2) and peroxiredoxin 1 and 4 (p1 and p4) along with protein and DANA oxidation
were examined to in postmortem brains of AD (n= 8) and normal (n= 7) subjects to evaluate the metabolism
dysfunction role in AD pathology.
Results: In spite of AMPK inhibitory control on mTOR, concurrent phosphorylation of AMPK and
mTOR (p-AMPK and p-mTOR) was observed in AD brains with high colocalization with
hyperphosphorylated tau. Mitochondrial antioxidant enzymes of SOD2 and p1 and p4 were substantially
decreased in p-AMPK, p-mTOR and p-tau positive cells along with higher levels of DNA and protein
Conclusion: Collectively, we conclude that AMPK and mTOR metabolic axis is highly activated in AD
brains. While the inhibitory link between AMPK and mTOR seems to be disrupted, we suggest
oxidative stress as the underlying mechanism for concurrent activation of AMPK and mTOR in AD.