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  • We and others have previously

    2022-01-25

    We and others have previously reported that neurons generated from iPSCs with genetic forms of AD recapitulate aspects of the disease, including increased Aβ peptide production in trisomy 21 and APP duplication neurons (Moore et al., 2015, Israel et al., 2012) and increased production of longer forms of Aβ in PSEN1 and APP mutant neurons (Moore et al., 2015, Muratore et al., 2014, Woodruff et al., 2016, Israel et al., 2012). We now report that AD mutations in APP and PSEN1 converge on disruption of the lysosome and autophagy system in human neurons. Given growing evidence from genome-wide association studies implicating the endolysosomal and autophagy systems in AD risk (Karch and Goate, 2015), these data suggest that dysfunction in these systems may represent an early pathogenic process in the disease. The contributions of the endolysosomal and autophagy systems to AD initiation and progression are currently unclear, with debate surrounding whether observed defects artesunate in those systems are causes or consequences of neuronal dysfunction and neurodegeneration (Nixon, 2017). Post-mortem analyses of the cerebral cortex have demonstrated enlarged early endosomes in neurons of individuals with trisomy 21 or APP duplication (Cataldo et al., 2000), as well as in transgenic mouse models expressing human APP, trisomy 21 fibroblasts, and various cell lines overexpressing different forms of APP (Nixon, 2017). Focal axonal swellings containing accumulations of lysosomal dense bodies and autophagic vacuoles have been observed in post-mortem artesunate samples of Alzheimer’s patients (Nixon, 2013, Nixon, 2017, Nixon et al., 2005), suggesting a failure of their axonal transport. We have found that mutations in APP and PSEN1 converge on defects in lysosome function and autophagy. The presence of these changes within relatively young neurons, combined with the ability to induce these phenotypes by acute gamma-secretase inhibition, indicates that these defects are a direct consequence of mutations in APP and PSEN1, and not an indirect effect of another degenerative process, such as protein aggregation. PSEN1 mutant neurons do not have early endosome defects, in contrast with APP mutant neurons. This is consistent with previous analysis from post-mortem studies showing that early endosomal abnormalities were not found in individuals with either PSEN1 or PSEN2 mutations, despite Aβ overproduction and amyloid plaque deposition (Cataldo et al., 2000). In addition, endosomal dysfunction was also absent in both primary fibroblasts from patients with PSEN1 mutation and neurons from PS1 and βAPP transgenic mice (Cataldo et al., 2000). Our finding that the different APP and PSEN1 mutations overlap in lysosome and autophagosome dysfunction suggest that the primary site of action of these mutant proteins is the lysosome, with endosomal changes being a secondary effect. Processing of APP by BACE1 in the endosome generates the APP C-terminal fragment (APP-β–CTF), which is in turn a substrate for γ-secretase in the lysosome. The role of APP-CTF in AD pathogenesis is the subject of considerable debate. Previous studies have suggested that intraneuronal accumulation of APP-CTF is a consequence of impaired lysosomal-autophagic degradation, rather than a cause of endolysosome or autophagy dysfunction (Peric and Annaert, 2015). In addition, a recent study showed that deletion of APP expression in mice deficient for all γ-secretases, by deletion of the genes encoding Aph1 subunits, failed to rescue progressive neurodegeneration (Acx et al., 2017). In that case, there was a general accumulation of many γ-secretase substrates, due to complete loss of γ-secretase function, which is in contrast to the hypomorphic character of autosomal dominant pathogenic mutations in PSEN1 (Moore et al., 2015, Chávez-Gutiérrez et al., 2012). Recent studies, however, have reported that intraneuronal aggregation of APP-CTF induced Aβ-independent lysosomal-autophagic pathology (Lauritzen et al., 2016, Jiang et al., 2016). We found that increasing intracellular APP-CTF by γ-secretase inhibition induced lysosomal-autophagic pathology: elevated levels of lysosomal LAMP1 and autophagosome LC3-II, increased density and size of LC3-positive puncta, and increased number of enlarged LAMP1-positive vesicles. In addition, γ-secretase inhibition markedly impaired axonal transport of lysosomes and led to autophagic defects.