Alzheimer’s Disease In The Brain: A Look Into Insulin Signaling Dysfunction

Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs cognitive functions, specifically memory, making it the leading cause of dementia.[4] Despite not knowing the specific etiology and pathogenesis of AD, the hallmarks are amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs).[1] Recent research has suggested that dysfunctional insulin signaling as well as neuroinflammation accelerate the progression of AD and its associated cognitive decline. Therefore, there is potential in targeting molecules involved in insulin’s signaling pathway including IDE, IRS, PI3K, mTOR, and GSK-3b for future treatment or prevention of AD.

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Figure 1. Two major hallmarks of Alzheimer’s disease: Aβ plaques and NFTs. [7]

Insulin Signaling – Why is it Important to AD?

Insulin, typically associated with glucose metabolism, has a regulatory role in the brain where it helps promote synaptic plasticity, neurotransmission, and neurogenesis. This is why insulin signaling is important and could be implicated in the progression of AD because when it is functioning properly improves cognitive function.

Insulin Resistance – A Possible Cause of AD?

Insulin resistance happens when the body becomes less responsive to the effects of insulin hormones. This can occur when there are lower levels of insulin binding to its receptors because insulin’s receptors can become desensitized. This can mean that even with insulin hormones being present, they might not bind to their receptors and activate their downstream pathways. Insulin resistance boosts oxidative stress, cytokines production (leading to neuroinflammation), and apoptosis. Insulin resistance leads to Alzheimer’s because it triggers a cascade of disrupted molecules in insulin’s signaling pathways, such as IDE, IRS, PI3K, mTOR, and caspases (Nrf2 and NF-kB).

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Figure 2. Role of the insulin signaling pathway (insulin and its various molecules) in neurodegeneration and Alzheimer’s disease. [5]

Amyloid-Beta to Aβ Plaques

Amyloid-beta peptides are cleaved from the glycoprotein amyloid precursor protein (APP) that plays a major role in neuronal development and signaling. Amyloid-β plaques occur when amyloid-beta proteins clump together outside of the cells. When plaques build up they may block cell-to-cell signaling at synapses or activate an immune response that causes excess cytokines to be released and may be a leading contributor to neuroinflammation in AD cases.

Figure 3. Formation of Amyloid-β plaques from the precursor APP protein. [3]

Tau Proteins to Neurofibrillary Tangles

In healthy neurons, tau proteins help to stabilize and coordinate microtubules, which help give neurons their structure. When insulin signaling is disrupted and PI3K pathways are not being activated properly, Akt does not phosphorylate GSK and inactivate it. When GSK is active it phosphorylates the tau proteins, causing them to break away from the microtubules and clump together into NFTs. Neurofibrillary tangles accumulate inside the cell and block neuron’s normal functioning, including the synaptic communication between neurons. Tau proteins leaving microtubules could also play a role in neurodegeneration because microtubules would not stabilize the cell structure and neuron extensions.