AKT panel
AKT Pathway Biomarkers: Linking GLP-1 Agonists to Neurotrophic Factor Signaling for Brain Health
The Growing Recognition of GLP-1RAs Beyond Metabolic Control
GLP-1RAs, originally designed to address metabolic disorders like type 2 diabetes, are now being investigated for their potential neuroprotective effects. This expanded therapeutic horizon stems from growing evidence demonstrating their ability to influence neuronal survival, growth, and function. The global market for these agonists is booming, indicating a significant investment in their potential.
The Concept of Neurotrophic Potential in Brain Health
Neurotrophic factors are essential proteins that support neuronal survival, growth, differentiation, and synaptic plasticity. Maintaining a healthy neurotrophic environment is critical for preventing neurodegeneration and promoting overall brain health.
Introducing AKT as a Key Mediator of Neurotrophic Effects
The AKT pathway, a central signaling hub within cells, plays a critical role in mediating various cellular processes, including survival, growth, and metabolism. Emerging research suggests that the AKT pathway acts as a crucial link between GLP-1RA action and neurotrophic factor signaling.
The PI3K/AKT Signaling Cascade: A Cellular Survival Superhighway
The PI3K/AKT signaling cascade is a complex network of protein interactions initiated by various extracellular signals, including growth factors and hormones. Upon activation, PI3K phosphorylates PIP2 to generate PIP3, a lipid second messenger that recruits AKT to the cell membrane, where it is activated.
AKT's Role in Promoting Neuronal Survival and Preventing Apoptosis
Activated AKT phosphorylates a multitude of downstream targets, inhibiting pro-apoptotic proteins and promoting cell survival pathways. This protective function is crucial in neuronal health, where apoptosis contributes to neurodegenerative processes.
AKT and Neurotrophic Factor Signaling: Enhancing Growth and Differentiation
AKT plays a critical role in mediating the effects of neurotrophic factors, including brain-derived neurotrophic factor (BDNF). By modulating downstream targets involved in protein synthesis and gene expression, AKT promotes neuronal growth and differentiation.
AKT's Impact on Synaptic Plasticity and Neuronal Function
Synaptic plasticity, the ability of synapses to strengthen or weaken over time, is fundamental to learning and memory. AKT influences synaptic plasticity by regulating AMPA receptor trafficking and function, thereby contributing to cognitive processes.
AKT and Mitochondrial Function: Powering Neuronal Resilience
Mitochondria, the powerhouses of cells, are essential for neuronal function and resilience. AKT supports mitochondrial health by regulating their biogenesis, dynamics, and function, ensuring efficient energy production and protection against oxidative stress.
GLP-1 Receptor Agonists: Mechanisms of Action and Neurotrophic Modulation
GLP-1R is expressed in various brain regions, including the hippocampus, cortex, and substantia nigra, suggesting a direct role in neuronal function. The presence of these receptors provides a target for GLP-1RAs to exert their neuroprotective effects.
How GLP-1R Activation Translates to Neurotrophic Benefits
Upon binding to GLP-1R, agonists initiate intracellular signaling cascades, including the crucial PI3K/AKT pathway. This activation triggers a cascade of events that ultimately promote neuronal survival, growth, and function.
AKT and Neurotrophic Factor Signaling: Enhancing Growth and Differentiation
Studies have shown that GLP-1R activation can enhance the expression and signaling of neurotrophic factors, such as BDNF. This increase in neurotrophic support contributes to a more robust and resilient neuronal environment. The increasing market for GLP-1 agonists, valued at USD 43.1 billion in 2024 and projected to reach USD 260.1 billion by 2034 [5], emphasizes their growing importance.
Mitigating Neuroinflammation and Oxidative Stress via GLP-1R Stimulation
Chronic neuroinflammation and oxidative stress are key contributors to neurodegeneration. GLP-1R activation has been shown to mitigate these damaging processes, offering further neuroprotection.
GLP-1RAs and the Protection of Specific Neuronal Populations (e.g., Dopaminergic Neurons, Cortical Neurons)
Research indicates that GLP-1RAs may selectively protect vulnerable neuronal populations, such as dopaminergic neurons in Parkinson's disease and cortical neurons crucial for cognitive function.
The Crucial Link: GLP-1RAs, AKT Activation, and Enhanced Neurotrophic Potential
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GLP1 and PPARg Treatment Response
Effects of GLP1 and PPARg agonists
Significant changes in response to Liraglutide (GLP-1 RA) and Pioglitazone (PPARg antagonist), two approved diabetic drugs. The changes in NDEs associated biomarkers were more strongly correlated to clinical outcome (depression and cognition) than the peripheral biomarkers of insulin resistance (glucose tolerance and fasting insulin)
