At the end of the last century, we had a clearer understanding of the disease characteristics of Alzheimer’s disease, such as plaque and tangles, neuronal death, and memory decline. But where did the disease come from and how did it start?
Alzheimer’s disease progresses very slowly. There are three hypotheses for the pathogenesis of the disease: the amyloid cascade hypothesis, the APOE4 hypothesis, and the Tau protein hypothesis.
In 1992, John Hardy of University College London proposed a bold hypothesis about the origin of the disease: the Amyloid cascade hypothesis. Hardy believes that the disease begins with the formation of beta amyloid protein in the brain, while tangles, neuronal cell death, memory loss, and dementia are secondary events caused by amyloid damage to the brain.
The accumulation of amyloid fragments produced by neurons outside the cells can lead to the formation of plaque. With time, plaque volume will gradually increase, and gradually begin to affect the communication between normal neurons, thereby affecting the normal function of neurons, triggering the formation of entanglement in neurons, and ultimately leading to the death of neurons.
The theory is supported by numerous evidences. For example, in 1995, scientists confirmed that mice carrying human APP mutant genes produce amyloid plaques in the brain and cognitive function declines. The amyloid cascade hypothesis not only makes relatively reasonable assumptions about the course of the disease, but more importantly it provides a practical target for the development of new drugs.
But in fact not everyone agrees with the amyloid hypothesis. Allen Roses of Duke University is one of them. In 1992, he and his colleagues found that the risk of early-onset and late-onset Alzheimer’s disease was significantly increased in APOE4 carriers. Carrying a copy of the gene increased the risk by a factor of 4, while carrying two copies of the gene would increase the risk by 12 Times.
APOE4 affects the normal uptake of blood glucose in the brain, leaving the brain in an energy-deficient state. Compared to APOE2 and APOE3 carriers, APOE4 carriers have lower blood glucose metabolism rates. The brain’s long-term lack of energy can lead to impaired neuronal function, which in turn leads to the formation of plaque and tangles that eventually lead to neuronal apoptosis.
Since neurons are difficult to regenerate, the process is not reversible and neurons can only die one by one. APOE4 theory has a clearer explanation of the origin of the disease than amyloid protein theory, but unfortunately it is difficult to develop new drugs against the APOE4 hypothesis compared to the amyloid protein hypothesis.
Both of the above two theories have many defects, which also provide the possibility of the Tau protein theory. A major function of the tau protein (Tubulin associated unit) is to maintain the stability of axon microtubules.
The hyperphosphorylation of tau protein leads to the formation of entanglement in neurons, which causes microtubules to fall off and affect the transport of neurotransmitters and other substances in neurons. It gradually leads to synaptic degeneration and axons disappear, leaving only the remaining The cell body where neurons reside.
The uniqueness of the Tau protein theory is that it does not explain the cause of the disease. Whether the disease causes amyloid protein or APOE4 or other factors, they all lead the neurons to a common fate: the abnormal phosphorylation of Tau protein and synaptic degeneration and neuronal death.
Although the Tau protein hypothesis can also provide a target for new drug development, one of the big drawbacks of the Tau protein hypothesis is that there is currently very little genetic evidence to support this hypothesis.