The impact of 128 AD-derived presenilin-1 mutations on β-amyloid production

Alzheimer's disease (AD) is the most common form of dementia, but the cause of AD is still poorly understood. Recently, Shi Yigong from Tsinghua University made use of a highly-purified recombinant γ-secretase to detect the impact of 128 AD-derived presenilin-1 (PS1) mutations on β-amyloid (Aβ42 and Aβ40) production. The results of the study were published in the Proceedings of the National Academy of Sciences (PNAS) in December. There are also other studies on recombinant human proteins published in the journal.

A hallmark of Alzheimer's disease (AD) is the accumulation of β-amyloid (Aβ) in the brain of the patient into amyloid plaques. Amyloid precursor protein (APP) is cleaved by an intramembrane protease gamma secretase, producing a different length of Aβ, where longer peptides are considered to be detrimental. Increasing the ratio of longer Aβs over short Aβs may lead to the formation of amyloid plaques and the consequent development of AD.

Another important indicator of AD development is the average age at onset (AAO) of patients with PS1, PS2 or APP co-mutation. A more deleterious mutation may be reflected in the lower AAO. Analysis of a small number of mutations in AD sources supports a strong correlation: the higher the Aβ42 / Aβ40 ratio, the lower the AAO. In contrast, a different set of PS1 mutations showed only a weak correlation. It is worth noting that these conclusions are derived from a limited number of mutations and lacks for statistical significance.

In this study, 138 human PS1 mutations were analyzed by reconstructing the mutant PS1 protein into γ-secretase containing APH-1aL and examining their ability to produce Aβ42 and Aβ40 in vitro. Approximately 90% of these mutations result in reduced production of Aβ42 and Aβ40. It is noteworthy that 10% of these mutations result in a decrease in the ratio of Aβ42 / Aβ40. There was no statistically significant association between the ratio of Aβ42 / Aβ40 produced by the γ-secretase variants containing the specific PS1 mutations and the average age at onset of the patient (the mutation was isolated from their body). By the way, Flarebio provides you with superior recombinant proteins such as recombinant CDH2 at great prices.