skip to primary navigationskip to content
 

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.

++++++++++++++++++

 

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.

combinedLogo x3 trans2018

 

Share this

Mature sperm small-RNA profile in the sparrow: implications for transgenerational effects of age on fitness

Single-cell transcriptome analyses reveal novel targets modulating cardiac neovascularization by resident endothelial cells following myocardial infarction

Derivation and maintenance of mouse haploid embryonic stem cells

Establishment of porcine and human expanded potential stem cells

Adapting machine-learning algorithms to design gene circuits

Lgr5+ stem/progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool

Identification of a regeneration-organizing cell in the Xenopus tail

Citrullination of HP1γ chromodomain affects association with chromatin

A critical but divergent role of PRDM14 in human primordial germ cell fate revealed by inducible degrons

A transmissible RNA pathway in honey bees

METTL1 Promotes let-7 MicroRNA Processing via m7G Methylation

A Secreted RNA Binding Protein Forms RNA-Stabilizing Granules in the Honeybee Royal Jelly

The Human Lung Cell Atlas - A high-resolution reference map of the human lung in health and disease

A Compendium of Mutational Signatures of Environmental Agents

Characteristics and homogeneity of N6-methylation in human genomes

Comparative Epigenomics Reveals that RNA Polymerase II Pausing and Chromatin Domain Organization Control Nematode piRNA Biogenesis

Pluripotency and X chromosome dynamics revealed in pig pre-gastrulating embryos by single cell analysis

Dorsal-ventral differences in neural stem cell quiescence are induced by p57KIP2/Dacapo

Crypt fusion as a homeostatic mechanism in the human colon

Link to full list on PubMed