P3 peptide

There is little information related to the p3 peptides composition and structure, and moreover most of it has to do with characteristics that concern to its role in Alzheimer's disease. p3 can be found as a 24 or 26 residues peptide, depending on which is gamma secretase's cleavage. The peptide which has 26 residues, presents the following sequence:

• VFFAEDVGSNKGAIIGLMVGGVVIAT^[3]

In relation to the secondary structure of p3 peptide, it is thought that after the cleavage by the α- and γ- secretases and extraction from the membrane it would convert quickly from the α-helix conformation it has when it is part of APPsα sequence to a β-hairpin structure. Then, this highly hydrophobic monomer would rapidly evolve into fibrils with no soluble intermediate forms, the ones related to amyloid’s structure. The main reason why p3 does not aggregate in amyloidogenic forms while Aβ does, is that the N-terminal domain Aβ_1–16, which is present in Aβ’s sequence but not in p3's one, is known to protect the hydrophobic core of the oligomers from being dissolved by the watered medium. So, p3 peptide oligomers would likely expose hydrophobic residues to water and would be less stable. As a consequence, p3 peptide structural determinants can assemble into fibrils, but no oligomeric forms have been identified. That is why p3 peptide represents the benign form of amyloid.^[4]

Energy plays a very important role in p3 peptides. While Aβ models have a strong negative energy, p3 oligomeric models have a positive one. Another characteristic that must be pointed out is that p3 peptides have more solvent-exposed hydrophobic surfaces (60%) than Aβ oligomers do (20%), so buried surface areas are not as big within p3 oligomers (30%) as they are within Aβ oligomers. These evidences show that the expected energy of the Aβ-based oligomeric models of p3 is always positive and that these models expose hydrophobic patches to the solvent and bury a small proportion of their accessible surface within the oligomeric intermediates. Having these facts into account, we can state that p3 oligomers' existence is thermodynamically unfavourable, which suggests that the p3 peptide cannot form stable soluble oligomers in the same way Aβ does. Solution of p3 cannot assemble into stable oligomers as Aβ_1–42 in the same concentration does. Therefore, it is very possible that p3 could not last long by itself, evolving rapidly into fibrillar forms that hide exposed hydrophobic patches.^[4]

p3 peptides have been analyzed in some researches with Western blot techniques. Primary antibodies were used to recognize Aβ_1–16 residues. Unexpectedly, it was discovered that the residues did not show any signal. This confirms the absence of N-terminal domain Aβ_1-16 in p3 peptides.^[4]

p3 peptide generates from the 17-40 or 17-42 sequence of the amyloid precursor protein (APP), which is a type I integral membrane protein concerned in neurons’ synapses in many human tissues. Under normal physiological conditions, APP is processed with three different proteolytic enzymes: α-, β- and γ-secretases. At first, APP molecule is cut by α-secretase or β-secretase, and it will produce two different molecules for each case. These products are respectively APPsα or α-CTFs, when cut by α-secretase, or APPsβ and β-CTFs, when processed by β secretase. APPs derivates are sent both to the extra-cell, while CTFs rest anchored to the plasmatic membrane. Then, α- and β-CTFs are processed by γ-secretase, resulting the peptides p3 and Aβ respectively and releasing in both cases a cytoplasmic peptide fragment known as the APP intracellular domain (AICD). Both p3 and Aβ are sent to the extracellular medium.^[4]