Alzheimer mutant speeds APP transport

Abstract

APPS198P segregates with rare familial forms of Alzheimer's disease and resides within exon 5, unlike 27 other mutations that reside in exons 16 or 17. In this issue, Zhang et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210313) show that the brains of APPS198P transgenic mice accumulate excess levels of Aβ. In cultured cells, APPS198P undergoes accelerated ER folding, leading to early arrival in late vesicular compartments, thereby enhancing generation of Aβ.

Insights from Sam Gandy and Michelle E. Ehrlich.

(A) Structure of human Alzheimer's APP with red arrow indicating location of S198P mutation described in Zhang et al. (2021). Panel A is reprinted with permission from Alzforum.org. (B) Structure of the Aβ domain of human APP. α-, β-, and γ-secretase cleavage sites are located near or within the Aβ domain. The positions and amino acid changes associated with 27 pathogenic mutations underlying familial Aβ proteinopathies are indicated by arrows leading from the one-letter code for the wild-type amino acid residue to that for each of the 27 pathogenic variants. In parentheses are the informal names of each (e.g., “Arctic” and “Dutch”). Panel B is reprinted with permission from Molecular Biology (Kulikova et al., 2015). (C) Current concepts in AD pathogenesis implicate Aβ proteinopathy, the immune-inflammatory response, and neuronal and synaptic integrity as important events in the initiation and/or progression of AD. Panel C is reprinted with permission from Biochimica et Biophysica Acta (BBA) – Biomembranes (Tan and Gleeson, 2019).