P13K and Alzheimers disease: The Domino Effect

The Domino Effect: Alzheimer’s disease follows a pathogenesis that includes a cascade of inflammation, synaptic dysfunction, and hyper-phosphorylation of Tau proteins. P13k is a serine/threonine protein kinase. This is an essential signaling component, especially in an irreversible neurodegenerative disease like Alzheimer’s.

(STK) serine/threonine kinase is responsible for cellular processing; within P13k, there is a catalytic subunit and a regulatory subunit. I like to think of the two as a relationship, similar to an employee and a manager. The catalytic subunit is an active site for phosphorylation and, in turn, enzymatically catalyzes a reaction. As the catalytic subunit responds to the regulatory subunit, the manager, its job is to facilitate, control, or inhibit these reactions.

P13K: The Trigger

• P13K is an enzyme that grows cells and initiates cell communication by transmitting signals. It is a critical for synaptic health.
• As P13k’s job is regulation, it can become uncontrolled or abnormal and, in turn, the body responds in vicious ways as the P13k pathway is principle in human disease
• The P13k/Akt pathway combustion accelerates neurodegeneration which triggers this cascade of events.

Akt Activation

• Akt activation is triggered by various cellular components involved in Alzheimer’s disease, stems primarily from Amyloid–B and Neurofibrillary tangles, which are neurodegenerative proteins found in patients with Alzheimer’s.
• The activation of PI3K facilitates Akt. 
• Serine/Threonine protein has a catalytic domain and a regulatory domain, involved in PI3K/Akt pathways and phosphoinositide.
• Phosphoinositide-dependent protein kinase-1 (PDK1) is responsible for the phosphorylation of Akt, which has three subtypes: Akt1, Akt2, and Akt3.

Phosphorylation of GSk-3B

• Akt phosphorylates Glycogen Synthase Kinase-3B (GSK-3B).
• GSk-3B propagates apoptotic signals and facilitates degradation.
• This, however, creates inactivation of GSk-3B.. which in turn accelerates Tau protein phosphorylation.

Tau Proteins

• Tau proteins are the main component of neurofibrillary tangles, which is the abnormal protein that promotes Alzheimer’s disease.
• Inactivation of GSK-3B causes the hyper-phosphorylation of Tau proteins.
• The hyper-phosphorylation of Tau proteins drives disease development.
• Tau proteins are essentially responsible for axonal transport and neurite growth, so when Tau becomes hyper-phosphorylated ,it cannot attach regularly to microtubules.
• Therefore, neurofibrillary tangles are formed, which affect cell communication and plasticity between neurons.

Alzheimers disease & P13K

• P13K Pathway is critical in a signaling cascade which develops apoptosis and neurodegeneration,
• Creates extracellular Amyloid- B plaques which are formed by amyloid cursor protein
• Creates intracellular neurofibrillary tangles occurring from hyper-phosphorylated Tau proteins.
• Amyloid-B and Neurofibrillary tangles are pathological marks that indicate Alzheimers disease. 
• In relation to therapeutic research, insulin signaling has been used as a neuromodulator to create ‘brain insulin resistance.’ which stemmed from the idea that dysfunctional insulin signaling was contributing to the symptomatology of Alzheimer’s disease.
• Dementia is a pathological disease, as Alzheimer’s follows the P13k/Akt pathway it produces hallmarks of AD, therefore, generates dysregulated brain insulin signaling.

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