Cell Reports
Volume 25, Issue 13, 26 December 2018, Pages 3647-3660.e2
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Article
Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer’s Disease

https://doi.org/10.1016/j.celrep.2018.11.095Get rights and content
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Highlights

  • APP and PSEN1 mutant neurons have deficits in lysosome proteolysis

  • BACE1 inhibition rescues lysosome and autophagy defects

  • PSEN1 mutant phenotypes are rescued by genetic deletion of APP

  • Lysosome and autophagy defects are causes of neuronal dysfunction in AD

Summary

Abnormalities of the endolysosomal and autophagy systems are found in Alzheimer’s disease, but it is not clear whether defects in these systems are a cause or consequence of degenerative processes in the disease. In human neuronal models of monogenic Alzheimer’s disease, APP and PSEN1 mutations disrupt lysosome function and autophagy, leading to impaired lysosomal proteolysis and defective autophagosome clearance. Processing of APP by γ-secretase is central to the pathogenic changes in the lysosome-autophagy system caused by PSEN1 and APP mutations: reducing production of C-terminal APP by inhibition of BACE1 rescued these phenotypes in both APP and PSEN1 mutant neurons, whereas inhibition of γ-secretase induced lysosomal and autophagic pathology in healthy neurons. Defects in lysosomes and autophagy due to PSEN1 mutations are rescued by CRISPR-knockout of APP. These data demonstrate a key role for proteolysis of the C-terminal of APP by γ-secretase in neuronal dysfunction in monogenic Alzheimer’s disease.

Keywords

endosome
lysosome
autophagy
axonal transport
live-cell imaging
Alzheimer’s disease

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