The mevalonate suppressor δ-tocotrienol increases AMPA receptor-mediated neurotransmission

Wei Wei, Sophie T. Yount, Zachary D. Allen, Katherine F. Bechdol, Weiming Xia, Huanbiao Mo, Angela M. Mabb

Research output: Contribution to journalArticlepeer-review


Synaptic dysfunction is a hallmark of aging and is found in several neurological disorders such as Alzheimer's disease. A common mechanism related to synaptic dysfunction is dysregulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which mediate excitatory neurotransmission and synaptic plasticity. Accumulating evidence suggests that tocotrienols, vitamin E molecules that contain an isoprenoid side chain, may promote cognitive improvement in hippocampal-dependent learning tasks. Tocotrienols have also been shown to reduce the secretion of β-amyloid (Aβ) and cholesterol biosynthesis in part by downregulating 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme that controls flux of the mevalonate pathway and cholesterol biosynthesis. We hypothesized that tocotrienols might promote cognitive improvement by increasing AMPA receptor-mediated synaptic transmission. Here, we found that δ-tocotrienol increased surface levels of GluA1 but not the GluA2 AMPA receptor subunit in primary hippocampal neurons. Unexpectedly, δ-tocotrienol treatment caused a decrease in the phosphorylation of GluA1 at Serine 845 with no significant changes in GluA1 at Serine 831. Moreover, δ-tocotrienol increased spontaneous excitatory postsynaptic current (sEPSC) amplitude and reduced the secretion of Aβ40 in primary hippocampal neurons. Taken together, our findings suggest that δ-tocotrienol increases AMPA receptor-mediated neurotransmission via noncanonical changes in GluA1 phosphorylation status. These findings suggest that δ-tocotrienol may be beneficial in ameliorating synaptic dysfunction found in aging and neurological disease.

Original languageEnglish (US)
Pages (from-to)112-119
Number of pages8
JournalBiochemical and Biophysical Research Communications
StatePublished - Jan 1 2023


  • Aging
  • Alzheimer's disease
  • AMPA receptor
  • Neurotransmission
  • Phosphorylation
  • Statins
  • Tocotrienols

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology


Dive into the research topics of 'The mevalonate suppressor δ-tocotrienol increases AMPA receptor-mediated neurotransmission'. Together they form a unique fingerprint.

Cite this