In this blog post, we take a closer look at how amyloid beta and tau proteins, which are believed to cause Alzheimer’s disease, destroy brain cells.
Alzheimer’s disease is the most common degenerative brain disease among the more than 50 causes of dementia, accounting for about 60% of all dementia cases. This disease is a type of “degenerative disease,” which occurs when cells that were functioning normally gradually deteriorate for no specific reason. In other words, Alzheimer’s disease is a disease in which brain cells are slowly destroyed and disappear over time, causing not only cognitive disorders such as memory loss, but also behavioral disorders such as incontinence.
To date, the cause of Alzheimer’s disease has not been fully identified. However, scientists have identified a relatively clear pathological mechanism, which they believe lies in the abnormal production and accumulation of amyloid beta (Aβ) proteins. In other words, when a well-functioning gene becomes abnormal, a misfolded protein called amyloid beta protein is produced, and this protein accumulates in our brains, gradually killing brain cells. This phenomenon is believed to be the key cause of Alzheimer’s disease.
So how is this amyloid beta protein produced, and why is it considered a key factor in Alzheimer’s disease?
A protein called amyloid precursor protein (APP) is present in the membranes of normal human brain cells. APP is known to be involved in the formation of synapses and synaptic connections between nerve cells, but its exact function has not yet been clarified. An important point is that a certain section of the APP protein contains amyloid beta protein (Aβ).
In a normal brain, an enzyme called alpha-secretase acts to split and break down the amyloid beta protein region in the APP protein in a normal manner. The broken pieces are naturally absorbed and removed, following the normal protein metabolism cycle in the brain.
However, in the brains of Alzheimer’s disease patients, instead of this normal pathway, two enzymes called beta-secretase and gamma-secretase act sequentially. At this point, the amyloid beta protein is cut out in its entirety while cutting both ends of APP.
The amyloid beta proteins produced in this way accumulate in the brain without being broken down or absorbed normally. These proteins clump together to form “aggregates,” which eventually settle in the brain tissue and become a kind of hard waste mass. These aggregates are called “amyloid plaques” and induce inflammatory reactions in the surrounding area.
These amyloid plaques exist around nerve cells, destroying them one by one and causing a decline in the function of the entire nervous system. Ultimately, these amyloid plaques are considered one of the representative pathological features of Alzheimer’s disease.
Furthermore, recent studies have found evidence that these misfolded amyloid beta proteins also affect the structure of another important protein called tau protein.
Inside brain cells, structures called microtubules extend like long highways and play a key role in transporting substances within cells. The tau protein is responsible for maintaining the stability of these microtubules. However, when amyloid beta proteins abnormally modify tau proteins, the tau proteins can no longer stabilize the microtubules and instead aggregate to form pathological structures called neurofibrillary tangles (NFTs).
These NFTs disrupt connections between cells, eventually leading to the death of nerve cells. In other words, two pathological processes occur simultaneously in the brains of Alzheimer’s patients. One is the accumulation of amyloid beta proteins and the formation of amyloid plaques, and the other is the modification of tau proteins and the formation of NFTs. These two pathological phenomena interact with each other and accelerate the death of brain cells.
In summary, in Alzheimer’s disease patients, amyloid beta protein is produced by the action of β- and γ-secretase, rather than the normal enzyme pathway (α-secretase). This protein does not undergo normal metabolism and accumulates in the brain, forming amyloid plaques that kill brain cells. At the same time, amyloid beta proteins induce tau protein deformation, which leads to the formation of neurofibrillary tangles (NFTs), disrupting connections between cells and eventually causing brain cells to die.
As such, Alzheimer’s disease is a complex and progressive disease that starts with a single protein problem and affects the entire brain. Although much research is still ongoing into the mechanism of this disease, which starts with memory loss and eventually leads to dementia that makes even daily life difficult, the pathological processes that have been discovered to date are enough to show how serious and complex this disease is.
