Chinese scientists discover a new mechanism for Alzheimer's disease

Alzheimer's disease (AD) is a common neurodegenerative disease that affects the cognitive and memory abilities of the brain. According to the Alzheimer's Association International, there are more than 50 million people living with dementia worldwide, and AD is the most common form of dementia, with the vast majority of patients having non-familial AD. For this reason, there is an urgent need for available treatments that can effectively treat AD.

This week, Yilin Chen's team at the Crossroads Research Center for Biology and Chemistry (Shanghai Institute of Organic Chemistry), Chinese Academy of Sciences, published a paper in Neuron that reveals a novel pathogenic mechanism of Alzheimer's disease. The team discovered the relationship between ApoE4, a pathogenic risk factor for non-familial AD, and the pathogenic mechanism of familial AD, thus pointing the way to potential therapies for AD.

One of the pathological features in the brains of AD patients is the presence of large amounts of amyloid (Aβ) plaques, but the relationship between amyloid plaques and cognitive and memory decline is still controversial. Much of the contemporary knowledge of the pathogenic mechanisms of AD comes from studies of familial AD (fAD), which is the basis for the amyloid hypothesis that excessive aggregation of Aβ accelerates the onset of AD.

Theoretically, amyloid precursor protein (APP) is sequentially cleaved by specific enzymes to produce peptides, and some mutations in the enzymatic activity centers of key γ-secretase (PS1 and PS2) accelerate the formation of amyloid plaques, eventually leading to fAD.

The theory is that amyloid precursor protein (APP) is sequentially cleaved by specific enzymes to produce peptides, and that some mutations in the enzymatic activity centers of key γ-secretase (PS1 and PS2) accelerate the formation of amyloid plaques, ultimately leading to fAD.

Despite considerable research on fAD, it accounts for only about 1% of all AD cases and about 99% of the other non-familial inherited sporadic AD (sAD), and patients with sAD do not carry the APP or PS1/2 mutations that cause fAD. In fact, apolipoprotein E4 (ApoE4) is the largest risk factor for sAD. About 14% of the population carries at least one ApoE4 gene. Compared to those carrying normal ApoE3, those carrying two copies of ApoE4 have a 10-fold increased risk of developing AD, and have an earlier age of disease and a much accelerated disease process before the age of 70. In contrast, another variant of ApoE2 significantly reduces the risk of developing AD.

Surprisingly, despite the contrasting effects on AD, the amino acid sequences of ApoE2, ApoE3 and ApoE4 proteins are very similar, differing by only 1-2 loci. Currently, it is not clear to the scientific community why different ApoE isoforms encoded by the same gene exert contrasting effects in the AD process. Moreover, it remains ambiguous whether there is a functional link between the sAD risk gene ApoE and the fAD causative genes APP and γ-secretase.

In the new study, Chen Yilin's team found that the pathogenic risk posed by ApoE isomers correlates with their direct and specific inhibition of the gamma-shearing activity of APP, proposing a new theory that ApoE isomers alter AD risk. The paper points out that it is the fact that ApoE2 has the strongest inhibitory activity, while ApoE4 loses that activity, that causes the two to possess completely different pathogenic consequences.

The theory directly links the risk genes of fAD and sAD functionally for the first time, suggesting that abnormalities in the gamma enzyme cleavage of APP are a common pathogenic cause of fAD and sAD.

A number of treatments for sAD based on the removal of Aβ have been clinically validated, but the therapeutic effect of this type of therapy has been limited and has only partially slowed the progression of AD. This is likely due to the fact that current antibody therapy only removes Aβ that has been secreted from the cells and the amyloid plaques that accumulate outside the cells. In fact, there is evidence that intracellular Aβ is also toxic, and antibody therapy has not been able to reach these Aβ.

In addition, the new study also found that ApoE active regions can precisely target neurons as well as Aβ-prone areas around amyloid plaques, and inhibit Aβ production in brain cells at source in a highly specific manner to achieve amyloid plaque reduction. Therefore, the above findings may lead to a new direction for potential AD therapies.