. Alzheimer's Disease "Non-amyloidogenic" p3 Peptide Revisited: A Case for Amyloid-α. ACS Chem Neurosci. 2020 May 22; PubMed.

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  1. This is an interesting paper that reports that Aβ17-40 (also known as P3) forms β-sheet amyloid fibrils with properties like that of its longer sibling, Aβ1-40. Aβ variants at the carboxyl terminus and amino terminus have been extensively investigated while P3 has been widely assumed to be “non-amyloidogenic,” perhaps because the first 16 amino acids of the first Aβ peptide isolated from brain were missing. This is despite early reports that show it is a major component of diffuse amyloid deposits from human brain (Gowing et al., 1994). However, these deposits were assumed to be “amorphous,” non-fibrillar forms of Aβ and thus non-toxic. In vitro, Kuhn, et al. now show that they form fibrils and oligomers that are similar to Aβ40 in terms of morphology, mobility on SDS PAGE and binding of Congo red and Thioflavin T.

    I think it would be interesting to re-examine the distribution of this specific P3 peptide and its association with AD and determine what effect BACE1 inhibitors have on the deposition of this Aβ variant. This would be facilitated by the development of antibodies that recognize the neoepitope created by α-secretase cleavage at the amino terminus of P3. It would also be interesting to test whether P3 and Aβ can co-assemble into the same fibril lattice or whether they make unique structures. 

    References:

    . Chemical characterization of A beta 17-42 peptide, a component of diffuse amyloid deposits of Alzheimer disease. J Biol Chem. 1994 Apr 15;269(15):10987-90. PubMed.

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