AKT, a kinase regulating numerous cellular processes in the brain, comes in three distinct varieties residing in different kinds of brain cells, and affecting brain health in very distinct ways, new research from University of Colorado at Boulder has found.

The discovery could lead to new, more targeted treatments for everything from glioblastoma to Alzheimer’s disease and schizophrenia.

Charles Hoeffer, assistant professor of integrative physiology at CU Boulder has been working for the past five to better understand AKT, which is ubiquitous in brain tissue and instrumental in enabling the brain to adapt to new experiences and lay down new memories.

Until now, scientists have known very little about what it does in the brain.

Memory Factory Protein

Discovered in the 1970s and known best as an “oncogene” (one that, when mutated, can promote cancer), AKT has more recently been identified as a key player in promoting synaptic plasticity, the brain’s ability to strengthen cellular connections in response to experience.

“AKT is a central protein that has been implicated in a bevy of neurological diseases yet we know amazingly little about it. Our paper is the first to comprehensively examine what its different forms are doing in the brain and where. Let’s say you see a great white shark and you are scared and your brain wants to form a memory of what’s going on. You have to make new proteins to encode that memory,"

Hoeffer said. AKT is one of the first proteins to come online, a central switch that turns on the memory factory.

But not all AKTs are created equal.

Key Discoveries

For the study, Hoeffer’s team silenced the three different isoforms, or varieties, of AKT in mice and observed their brain activity.

[caption id=“attachment_94297” align=“aligncenter” width=“680”]Cell-type-specific expression of AKT isoforms in hippocampal area CA1. Cell-type-specific expression of AKT isoforms in hippocampal area CA1.
(a). AKT1 was mainly expressed in neuronal cell bodies, indicated by co-localization with NeuN.
Certain neurons in the pyramidal layer, stratum oriens and molecular layer showed greater expression levels of AKT1 (yellow arrows).
AKT2 was specifically expressed in astrocytes, shown by co-localization with the astrocyte marker GFAP. AKT3 co-localized with NeuN like AKT1 but was also expressed in the stratum radiatum, most likely within dendrites.
(b) Higher magnification showed no specific co-localization of AKT1 with GFAP and that certain neurons in the stratum oriens expressed high levels of AKT1 (yellow arrows).
AKT2 was mainly expressed in the cell bodies of astrocytes. AKT3 showed high expression levels in neuronal cell bodies and dendrites and some expression in astrocytes.
Credit: Josien Levenga, et al. CC-BY[/caption]

They made a number of key discoveries.

AKT2 is found exclusively in astroglia, the supportive, star-shaped cells in the brain and spinal cord that are often impacted in brain cancer and brain injury.

“That is a really important finding. If you could develop a drug that targeted only AKT2 without impacting other forms, it might be more effective in treating certain issues with fewer side-effects,"

said co-author Josien Levenga, who worked on the project as a postdoctoral researcher at CU Boulder.

The researchers also found that AKT1 is ubiquitous in neurons and appears to be the most important form in promoting the strengthening of synapses in response to experience, aka memory formation. This finding is in line with previous research showing that mutations in AKT1 boost risk of schizophrenia and other brain disorders associated with a flaw in the way a patient perceives or remembers experiences.

AKT Inhibitors

AKT3 appears to play a key role in brain growth, with mice whose AKT3 gene is silenced showing smaller brain size.

“Before this, there was an assumption that they all did basically the same thing in the same cells in the same way. Now we know better,"

Hoeffer said.

He notes that pan-AKT inhibitors have already been developed for cancer treatment, but he envisions a day when drugs could be developed to target more specific versions of the protein (AKT1 enhancers for Alzheimer’s and schizophrenia, AKT2 inhibitors for cancer), leaving the others forms untouched, preventing side-effects.

[caption id=“attachment_94298” align=“aligncenter” width=“680”]AKT1 and AKT3 AKT1 and AKT3 are involved in mGluR-LTD.
(a) Double Akt1 and Akt3 mutant (cA1F/A3K) mice with Cre-mediated removal of both Akt1 alleles in the Akt3 KO background were generated with WT littermate controls by breeding Camk2a-Cre::Akt1loxP/+/Akt3+/- female mice with Akt1loxP/+/Akt3+/- males.
(b,c) Western blot analysis showing significantly reduced AKT1 levels and no AKT3 expression in the hippocampus of cA1F/A3K mice compared with WT mice (AKT1 levels: t(6)=3.802, p=0.008).
(d) Immunostaining confirming reduced neuronal AKT1 expression by Camk2a-driven Cre removal of Akt1 in the hippocampus, especially in the pyramidal cell body layer of CA1.
(e) mGluR-LTD is enhanced in cA1F/A3K hippocampal slices (F(1,30)=7.923, p=0.009), n = 16 slices/group, 5 mice/group.
(f,g) Western blot analysis showing significantly increased phosphorylation of ERK Thr202/Tyr204 and S6 S235/236 but not TSC2 S939 in cA1F/A3K hippocampal slices at 60 min post-DHPG, while WT slices had no differences.
Credit: Josien Levenga, et al. CC-BY[/caption]

More animal research is underway to determine what happens to behavior when different forms of the protein go awry.

“Isoform specific treatments hold great promise for the design of targeted therapies to treat neurological diseases with much greater efficacy and accuracy than those utilizing a one-size-fits-all approach. This study is an important step in that direction,"

the authors conclude.

Funding for the work was provided by the National Institutes of Health, Sie Foundation, Alzheimer’s Association, Simons Foundation, Linda Crnic Institute for Down Syndrome, and the National Alliance for Research on Schizophrenia and Depression.

Josien Levenga, Helen Wong, Ryan A Milstead, Bailey N Keller, Lauren E LaPlante, Charles A Hoeffer AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity eLife 2017;6:e30640

Top Image: NIMR Wellcome Images.jpg

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