Protective mutation - A673T
Surprise!
Although amyloid-β precursor protein (APP) mutations are generally associated with AD, John et al. (2003) found an APP mutation that can protect you against the disease.
It is in close proximity of the β-cleavage site of APP and is a point mutation from A to T at position 673. This reduces the cleavage of APP by BACE and hence the formation of amyloid fibres and plaques (Figure 1).
Although amyloid-β precursor protein (APP) mutations are generally associated with AD, John et al. (2003) found an APP mutation that can protect you against the disease.
It is in close proximity of the β-cleavage site of APP and is a point mutation from A to T at position 673. This reduces the cleavage of APP by BACE and hence the formation of amyloid fibres and plaques (Figure 1).
Evidence: Jonsson et al. (2012)’s study
Genotyping studies on Icelanders from different age groups
- Classification of subjects into A673T and non A673T (wild type)
- Significantly higher cognitive function in A673T carriers as compared to non A673T carriers, as measured by CPS (Note: CPS is an index that indicates cognitive function, the higher means the worse.)
- Cognitive function remains relatively stable with age in A673T carriers (Figure 2)
Transfection of cDNA into 293 T cells
- ELISA quantification of BACE1 cleavage products, sAPPβ, Aβx-40 and Aβx-42
- Significantly decrease in these products, as compared to wild type (WT), P<0.05 (Figure 3)
Evaluation
How novel is the discovery of A673T?
Is it truly a medical breakthrough?
Yes.
- The data suggest that A673T mutation is associated with a decrease in BACE cleavage products, sAPPb, Aβx-40 and Aβx-42.
- Genetic data indicate that A673T mutation protects cognitive function in the elderly.
- Therefore, A673T may protect against cognitive degeneration by decreasing the amount of BACE cleavage products.
- Hence A673T may decrease the incidence of AD by preventing the formation, aggregation and deposition of amyloid fibres in the brain, according to John et al. (2003)’s model.
How novel is the discovery of A673T?
- It is novel because it has not been described in the news and the literature until recently. All the genetic studies before this discovery were about unfavorable APP mutations that predisposed one to AD.
- The lack of comparable studies also suggests that the discovery is novel.
Is it truly a medical breakthrough?
Yes.
- This is the first time the function of BACE was validated in humans. All previous validation studies were conducted predominantly on mice.
- The idea that A673T mutation decreases APP cleavage by BACE leads on to the synthesis of BACE inhibitors to treat AD. BACE inhibitors have the potential to slow down cognitive degeneration, because it inhibits the amyloid fibres producing precursors.
- No drugs can slow down the progression or cure the disease at the moment. All therapies so far (e.g. speech therapy) can only treat the symptoms of the disease. So BACE inhibitors sound more promising as an AD treatment.
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