Previous work, mainly in non-neuronal systems, indicated isoform-specific substrate specificity. Both the α1 and α2 isoforms are expressed in most tissues, including the brain, for regulation of energy homeostasis. The kinase catalytic subunit of AMPK exists in two isoforms: α1 and α2, which are encoded by distinct genes located in different chromosomes. Emerging evidence also links AMPK dysregulation to diverse neurological diseases characterized by cognitive impairments, including Alzheimer’s disease (AD), albeit with conflicting results about whether activation/phosphorylation of AMPKα in brain is beneficial or detrimental for cognition and synaptic function. Several studies indicated that AMPK is involved in hippocampal long-term potentiation (LTP), a major form of synaptic plasticity and cellular model for memory. The brain has an extremely high metabolic rate and functions of neurons depend on sustaining energy levels. Furthermore, AKT is a negative regulator of AMPK, leading to decreased phosphorylation of Thr172. The major kinases phosphorylating Thr172 include LKB1, a tumor suppressor that appears to be constitutively active the Ca 2+/calmodulin-dependent protein kinase CaMKKβ, stimulated by increased cytosolic Ca 2+ and TAK1 (also known as MAP3K7 or MEKK7), a protein kinase activated by cytokines. Phosphorylation is quantitatively much more important than the allosteric activation because it causes at least a 50- to 100-fold increase in AMPK activation. AMPK is activated in response to low energy states, and can be activated via either allosteric activation mediated by the γ subunit or phosphorylation of the α subunit at Thr172. Mammalian AMPK is a heterotrimeric complex composed of a catalytic α subunit, and regulatory β and γ subunits. Mounting evidence has established that the AMP-activated protein kinase (AMPK) is a key sensor/regulator at the molecular level to maintain energy homeostasis. In summary, we demonstrate here that brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation, providing molecular mechanisms linking metabolism, protein synthesis, and cognition.Īccurate control of energy metabolism to balance energy demand and supply is critically important for function and survival of all organisms. Importantly, L-LTP failure and cognitive impairments displayed in AMPKα2 cKO mice were alleviated by suppressing PERK activity pharmacologically or genetically. Biochemical studies revealed unexpected findings that repression of AMPKα2 resulted in increased phosphorylation of mRNA translational factor eIF2α and its kinase PERK. Electron microscope imaging demonstrated reduced postsynaptic density formation and fewer dendritic polyribosomes in hippocampi of AMPKα2 cKO mice.
Further, AMPKα2 cKO mice exhibited decreased dendritic spine density and abnormal spine morphology in hippocampus. AMPKα2 cKO but not AMPKα1 cKO displayed impaired cognition and hippocampal late long-term potentiation (L-LTP). We generated conditional knockout mice in which brain AMPKα isoforms are selectively suppressed (AMPKα1/α2 cKO), and determined the isoform-specific effects in mice of either sex on cognition and synaptic plasticity. The two isoforms of the AMPK catalytic subunit (AMPKα1 and α2) are both expressed in brains, but their roles in cognition are unknown. Diwali celebrations are varied and diverse, but often include fireworks, exchanging sweets and gifts, and a focus on renewal and prosperity. There is a modest surcharge on both of these departures to accommodate the popularity of accommodations and other services during this period.The AMP-activated protein kinase (AMPK) is a molecular sensor to maintain energy homeostasis. Diwali is the five day Festival of Lights being Sun, Nov 12 in 2023. Held in the spring, it is a vibrant celebration of love often featuring colored powder liberally shared. Holi is the Festival of Colors and will be Weds, March 8 in 2023. Two of our departures will occur during Indian festivals. Before booking your international airline tickets, check with us to ensure the trip and extension are confirmed above minimum participation requirements. Please let us know as soon as possible if you are interested in taking the extension. The minimum group size for us to operate the extension is 4 guests. The cost of the Taj Mahal extension is $390 per person based on double occupancy. The listed price of the trip is per person based on double occupancy.
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