summary: Scientists have discovered a link between two types of Alzheimer’s disease, highlighting how the more common form of the disease is rarely linked. The discovery could help researchers develop new treatments for Alzheimer’s disease, which affects millions of people worldwide.

source: Chinese Academy of Sciences

Alzheimer’s disease (AD) can be divided into the rare familial early-onset Alzheimer’s disease (fAD) and the common sporadic late-onset (sAD) that impair the memory and cognitive functions of older adults worldwide.

While the formation of amyloid plaques is a common brain pathology in both diabetes mellitus and the disorder, the genetics of fAD and sAD are distinct, and it could be argued that different pathogenesis mechanisms may be involved; Therefore, different treatment strategies should be considered. In this regard, the billion dollar question is whether targeting amyloid plaques is the right strategy for treating common seasonal affective disorder.

In a study published in nervousProfessor Chen Yilin’s group from the Interdisciplinary Research Center in Biology and Chemistry, Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences, provided an answer to this question.

Researchers have uncovered a mechanistic relationship between the most common risk factor for seasonal affective disorder, ApoE4, and pathogenic genetic factors of FAD that directly promote the formation of amyloid plaques, providing a missing link between common seasonal affective disorder and rare fads.

Identified mutations in genes encoding enzymes to process amyloid precursor protein (APP), including APP itself and the cleavage modules γ-secretase (PS1 and PS2), directly promote the development of fAD by accelerating the formation of amyloid plaques.

However, 99% of SAD sufferers do not carry mutations in APP or PS1/2. In contrast, individuals who carry two copies of ApoE4 have a tenfold increased risk of developing tardive social anxiety disorder compared to subjects with normal ApoE3. Another variant, ApoE2, can significantly reduce the risk of seasonal affective disorder.

This indicates a brain
Another variant, ApoE2, can significantly reduce the risk of seasonal affective disorder. The image is in the public domain

The striking effect of different ApoE variants on sAD development has also been a long-standing puzzle in the field as the amino acid sequences of ApoE2, ApoE3 and ApoE4 differ by only 1–2 amino acid residues.

The authors have found a direct and differential inhibition of the γ-cleavage of APP by different isoforms of ApoE, and have demonstrated how ApoE isomers may alter the risk of SAD. ApoE2 shows the strongest inhibitory activity on γ-cleavage of APP, while ApoE4 loses this activity.

This finding provides the missing link between risk genes for chronic affective disorder and seasonal affective disorder, suggesting that abnormal cleavage of APP is a common pathogen for dominant disorder and seasonal affective disorder. This study proposes the C-terminal region of ApoE as a substrate-specific β-secretase inhibitor with therapeutic potential.

About this genetics and Alzheimer’s disease research news

author: Liu Jia
source: Chinese Academy of Sciences
communication: Liu Jia – Chinese Academy of Sciences
picture: The image is in the public domain

Original search: Closed access.
“Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4” by Chen Yelin et al. nervous

a summary

Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4


  • ApoE isoforms differentially inhibit γ-cleavage of APP in cell-autonomous behaviour
  • The C-terminal region of ApoE inhibits beta-secretion with substrate specificity
  • Neuronal expression of the C-terminal region of ApoE attenuates plaque burden in 5 × FAD mice
  • The C-terminal region directs the migration of ApoE from neurons to the amyloid plaque


Abnormal γ-secretase activity is associated with most presenilin mutations that underlie familial Alzheimer’s disease (fAD). However, the role of γ-secretase in the more prevalent sporadic Alzheimer’s disease (sAD) remains unaddressed.

Here, we report that human apolipoprotein E (ApoE), the most important genetic risk factor for SAD, interacts with and substrate-specifically inhibits γ-secretase in cell-autonomous behavior through its C-protected region (CT).

This ApoE CT-mediated inhibitory activity is differentially permeated by different isoforms of ApoE, resulting in a rank order of potency of ApoE2 > ApoE3 > ApoE4 that is inversely associated with associated AD risk. Interestingly, in an AD mouse model, ApoE CT neurons migrate to subtelomeric amyloid plaques from other regions and relieve plaque burden.

Together, our data reveal a hidden role for ApoE as a γ-secretase inhibitor with substrate specificity and suggest that subtle inhibition of γ-secretase by ApoE may protect against the risk of SAD.

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