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26.12.18 Lysosome and autophagy defects are causes of neuronal dysfunction in Alzheimer's Disease

last modified Jan 03, 2019 03:25 PM
The Livesey lab show that single gene defects in early onset Alzheimer's lead to disrupted lysosome and autophagosome function in human cortical neurons
26.12.18 Lysosome and autophagy defects are causes of neuronal dysfunction in Alzheimer's Disease

(Graphical abstract from the paper)

Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer’s Disease

Hung COY & Livesey FJ (2018) Cell Reports, Volume 25, Issue 13, P3647-3660.E2.  DOI: 10.1016/j.celrep.2018.11.095

 

 Highlights from the paper

  • 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 from the paper

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.

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Read more about research in the Livesey lab.

In 2019 Rick Livesey's lab will move to a new home at the UCL Great Ormond Street Institute of Child Health. Rick is now Chair of Stem Cell Biology there.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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