▎WuXi AppTec content team editor
Alzheimer's disease (AD) is a common neurodegenerative disease that affects the brain's ability to recognize and remember. According to the Alzheimer's International Association, there are more than 50 million people with dementia worldwide, and AD is the most common form of dementia, with the vast majority of patients having non-familial inherited AD. For this reason, there is an urgent need for available methods that can effectively treat AD.
This week, Chen Yulin's team from the Interdisciplinary Research Center for Biology and Chemistry (Shanghai Institute of Organic Chemistry) of the Chinese Academy of Sciences published a paper in Neuron, revealing a completely new pathological mechanism of Alzheimer's disease. The research team discovered the relationship between the pathogenic risk factor ApoE4 of non-familial inherited AD and the pathogenic mechanism of familial hereditary AD, thus pointing the direction for potential therapies for AD.
One of the pathological features in the brain of AD patients is the presence of a large number of amyloid (Aβ) plaques, but the relationship between amyloid plaques and cognitive and memory decline is still controversial. At present, the understanding of the pathogenic mechanism of AD mostly comes from the study of familial inherited AD (fAD), which is also the basis for the amyloid hypothesis, that is, excessive aggregation of Aβ will accelerate the occurrence of AD.
Theoretically, amyloid precursor proteins (APP) are continuously cleaved under the action of special enzymes to produce peptides, while in the key γ secretase's digestion-active centers (PS1 and PS2), some mutations accelerate the formation of amyloid plaques, eventually leading to fAD.
Although fAD has been studied a lot, it accounts for only about 1% of all AD cases, and about 99% is non-familial sporadic AD (sAD), and patients with sAD do not carry the APP or PS1/2 mutation that causes fAD. In fact, apolipoprotein E4 (ApoE4) is the biggest risk factor for sAD. About 14 percent of the population carries at least one ApoE4 gene. People with 2 copies of ApoE4 have a 10-fold increased risk of AD compared with people with normal ApoE3, and the age of disease is advanced to before the age of 70, and the disease process is greatly accelerated. Another variant, ApoE2, significantly reduces the risk of AD.
▲ApoE2 will reduce the production of amyloid (Image source: Reference [1])
Surprisingly, although the effects on AD are very different, the amino acid sequences of ApoE2, ApoE3, and ApoE4 proteins are very similar, with only 1-2 different sites. At present, it is not clear to the scientific community why different ApoE isoforms encoded by the same gene play diametrically opposite effects in the AD process. In addition, whether there is a functional link between the sAD risk gene ApoE and the fAD pathogenic gene APP and γ secretase is still ambiguous.
▲The study revealed the pathogenic mechanism related to the pathogenic risk factor ApoE4 of non-familial inherited AD (Image source: Reference [1])
In the new study, Chen Yulin's team found that the pathogenic risk posed by the ApoE isomer was related to its direct and specific inhibition of the γ-shear activity of the APP, and proposed a new theory that the ApoE isomer changed the risk of AD. The paper pointed out that it is precisely because ApoE2 has the strongest inhibitory activity and ApoE4 loses this activity, which leads to completely different pathogenic consequences for both.
This theory directly links the risk genes of fAD and sAD for the first time, suggesting that abnormal γ digestion of APP is the common cause of fAD and sAD.
▲ApoE interacts with APP and γ secretase (Image source: Reference [1])
At present, some treatments based on Aβ clearance of sAD have been clinically verified, but the therapeutic effect of this type of therapy is limited and can only partially slow down the deterioration of AD. The study speculates that this may be because current antibody therapy can only remove Aβ that has been secreted from cells and the amyloid plaques that accumulate outside the cell. In fact, there is evidence that intracellular Aβ is also toxic, and antibody therapy cannot yet reach these Aβs.
In addition, the new study also found that the active region of ApoE can accurately locate neurons and Aβ high incidence areas around amyloid plaques, and inhibit the production of Aβ in brain cells from the source in a highly specific way to achieve the purpose of reducing amyloid plaques. Therefore, the above findings may lead to a completely new direction for potential AD therapies.
Dr. Hou Xianglong and doctoral student Zhang Xuexin of the Chen Yulin Research Group of the Interdisciplinary Research Center of Biology and Chemistry (Shanghai Institute of Organic Chemistry) of the Chinese Academy of Sciences are the first authors of the paper, and Professor Chen Yulin and Associate Professor Geng Yang are the corresponding authors of the paper. This work was assisted and supported by researchers Zhang Zairong and Wang Wenyuan from the Interdisciplinary Center. The research was supported by the Chinese Academy of Sciences and the Shanghai Science and Technology Major Special Fund.
Resources:
[1] Differential and substrate-specific inhibition of g-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4. Neuron (2023). DOI: https://doi.org/10.1016/j.neuron.2023.03.024