The clipping of APP produces two types of amyloid beta peptide--one 40 amino acid units long (Ab40) and one 42 units long (Ab42). Circumstantial evidence has suggested that Ab42 is the "stickier" of the two forms, and underlies the pathology of the disease.
Now, researchers led by Eileen McGowan and Todd Golde of the Mayo Clinic College of Medicine report in the July 21, 2005, issue of Neuron definitive proof that Ab42 is, indeed, the culprit molecule. In their experiments, they created transgenic mice that overproduced either Ab40 or Ab42 in the absence of overproduction of APP. Thus, they could precisely study the role of each of these molecules in AD pathology.
Their studies of the mice revealed that the Ab40 mice showed little amyloid disease pathology in the animals' brains, while the Ab42 mice showed extensive accumulation of amyloid plaque and resulting neural damage. What's more, when the researchers crossed the Ab42 mice with those producing mutant APP, they saw a massive increase in amyloid deposition that was more than the additive effect of the two mutations.
The researchers pointed out that test tube studies have shown that Ab42 aggregates more readily. "Thus, the simplest explanation for the complete lack of pathology in the [Ab40] mice would be the relative inability of Ab40 to initiate nucleation events capable of promoting amyloid deposition," they wrote.
One question the new transgenic mice might help address, wrote the researchers, is whether Ab peptide does damage i