Onset and Progression of Alzheimer's Disease Through the Cofilin-Actin Rod Mechanism
Step 1: Oxidative stress and Amyloid-Beta Plaque Formation
Any aspect of stress, specifically due to excess oxidation, compromising the integrity of brain cells may lead to a cascade of events linked to the onset of Alzheimer’s Disease. When oxidative stress increases within the brain, it is accompanied by an increased production of a naturally occurring protein called Amyloid-Beta, which is causal of Amyloid-Beta plaques found in those with Alzheimer’s Disease.
Step 3: Neuroinflammation and Tau- Tangle Progression
The brain’s response to inflammation caused by cofilin- actin rod accumulation occures through the formation of tau. Tau is a stabilizing protein found in neurons which functions to stabilize microtubules throughout the neuron. In those with Alzheimer’s Disease, tau is hyperphosphorylated, resulting in the self assembly of tau tangles. These tangles of Tao protein are much more prevalent in those with Alzheimer’s compared to those without the disease. While tau production and tangles are not thought to be causative of Alzheimer’s Disease, they are seen as a use for diagnosis.
Step 2: Amyloid-Beta Plaque Formation Leads to Cofilin-Actin Rod Formation
White arrows point to rods.
Increased production of Amyloid-Beta proteins is correlated with formation of cofilin-actin rods. Cofilin is a naturally occurring protein in the brain, however, when oxidized, it forms rod shaped structures within axons and dendrites throughout the brain, leading to decreased neuronal cell signaling. It is predicted that cofilin-actin rod formation triggers a neuroinflammatory response in the brain, commonly found in neurodegenerative diseases such as Alzheimer’s Disease.
Pattern of Tau-Tangle Formation
In Alzheimer’s Disease, tangles aggregate in a specific pattern throughout the brain correlating with the brain’s pattern of memory loss as well as symptoms of Alzheimer’s Disease. The main area in which the brain is affected by Alzheimer’s Disease, mirrored with tau tangle production, is within the cortex, and is also concentrated in areas involved in learning/memory and thinking/planning. The tangles have also been shown to affect areas of the brain responsible for speaking and understanding speech, as well as proprioception. Because of the mass amount of cell inhibition due to the formation of cofilin-actin rods and consequently the tau tangle formations, the cells eventually atrophy and die, leading to the shrinkage of the brain’s cortex and common symptoms of Alzheimer’s Disease which were previously stated.