Missing link between risk genes associated with Alzheimer’s disease discovered

summary: Scientists have discovered a link between two types of Alzheimer’s disease and have figured out how the most common type of Alzheimer’s disease is related to the rarer type. The discovery could help researchers develop new treatments for Alzheimer’s disease, which affects millions of people around the world.

sauce: Chinese Academy of Sciences

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

Although amyloid plaque formation is a common brain pathology in both fAD and sAD, it can be argued that the genetics of fAD and sAD are distinct and may involve different pathogenic mechanisms. Therefore, different treatment strategies should be considered. In this regard, there is the billion-dollar question of whether targeting amyloid plaques is the right strategy for treating sAD in general.

In a study published in neuronProfessor Chen Yelin’s group at the Interdisciplinary Center for Biochemical Studies, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, provided an answer to this question.

Researchers have elucidated a mechanistic relationship between ApoE4, the most common virulence risk factor for sAD, and genetic factors in fAD that cause the disease that directly promote the formation of amyloid plaques, leading to a common provided the missing link between sAD and rare fAD.

Specific mutations in genes encoding enzymes for processing amyloid precursor protein (APP), including APP itself and the γ-secretase cleavage subunits (PS1 and PS2), have been associated with fAD by accelerating the formation of amyloid plaques. directly promotes the occurrence of

However, approximately 99% of common late-onset sAD do not have mutations in APP or PS1/2. In contrast, individuals with her two copies of ApoE4 have a 10-fold higher risk of developing late-onset sAD compared with those with normal her ApoE3. Another variant, her ApoE2, can significantly reduce the risk of sAD.

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

The researchers found direct and differential inhibition of APP gamma-cleavage by different ApoE isoforms and demonstrated how ApoE isomers alter the risk of developing sAD. ApoE2 exhibits the strongest inhibitory activity against γ-cleavage of APP, whereas ApoE4 loses this activity.

This finding provides a missing link between fAD and sAD risk genes and suggests that aberrant γ-truncation of APP is a common virulence cause of fAD and sAD. This study suggests that the C-terminal region of ApoE is a substrate-specific γ-secretase inhibitor with therapeutic potential.

About this genetics and Alzheimer’s research news

author: Liu Jia
sauce: Chinese Academy of Sciences
contact: Liu Jia – Chinese Academy of Sciences
image: image is public domain

Original research: closed access.
“Differential substrate-specific inhibition of γ-secretase by the C-terminal regions of ApoE2, ApoE3, and ApoE4by Chen Yeling et al. neuron

overview

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

highlight

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

summary

Abnormally low 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 common sporadic AD (sAD) remains unresolved.

Here, human apolipoprotein E (ApoE), the most important genetic risk factor for sAD, interacts with γ-secretase and, via its conserved C-terminal region (CT), exhibits substrate specificity in a cell-autonomous manner. report to inhibit it.

This ApoE CT-mediated inhibitory activity is differentially impaired in different ApoE isoforms, and the ApoE2 > ApoE3 > ApoE4 potency rank order is inversely correlated with associated AD risk. Interestingly, in an AD mouse model, neuronal her-ApoE CT migrates from other regions to amyloid plaques in the subiculum, reducing plaque burden.

Together, our data reveal a hidden role for ApoE as a γ-secretase inhibitor with substrate specificity, suggesting that this precise γ-inhibition by ApoE may protect against the risk of sAD. It suggests that there is