Dataset Information

Altered ?-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease.

ABSTRACT: 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 ?-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 ?-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 ?-secretase in neuronal dysfunction in monogenic Alzheimer's disease.

SUBMITTER: Hung COY

PROVIDER: S-EPMC6315085 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

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

Hung Christy O Y COY Livesey Frederick J FJ

Cell reports 20181201 13

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 lysos ...[more]

PMID: 30590039

Similar Datasets

Project description:The amyloid β-peptide (Aβ) of Alzheimer's disease (AD) is generated by proteolysis within the transmembrane domain (TMD) of a C-terminal fragment of the amyloid β protein-precursor (APP CTFβ) by the γ-secretase complex. This processing produces Aβ ranging from 38 to 49 residues in length. Evidence suggests that this spectrum of Aβ peptides is the result of successive γ-secretase cleavages, with endoproteolysis first occurring at the ε sites to generate Aβ48 or Aβ49, followed by C-terminal trimming mostly every three residues along two product lines to generate shorter, secreted forms of Aβ: the primary Aβ49-46-43-40 line and a minor Aβ48-45-42-38 line. The major secreted Aβ species are Aβ40 and Aβ42, and an increased proportion of the longer, aggregation-prone Aβ42 compared to Aβ40 is widely thought to be important in AD pathogenesis. We examined TMD substrate determinants of the specificity and efficiency of ε site endoproteolysis and carboxypeptidase trimming of CTFβ by γ-secretase. We determined that the C-terminal negative charge of the intermediate Aβ49 does not play a role in its trimming by γ-secretase. Peptidomimetic probes suggest that γ-secretase has S1', S2', and S3' pockets, through which trimming by tripeptides may be determined. However, deletion of residues around the ε sites demonstrates that a depth of three residues within the TMD is not a determinant of the location of endoproteolytic ε cleavage of CTFβ. We also show that instability of the CTFβ TMD helix near the ε site significantly increases endoproteolysis, and that helical instability near the carboxypeptidase cleavage sites facilitates C-terminal trimming by γ-secretase. In addition, we found that CTFβ dimers are not endoproteolyzed by γ-secretase. These results support a model in which initial interaction of the array of residues along the undimerized single helical TMD of substrates dictates the site of initial ε cleavage and that helix unwinding is essential for both endoproteolysis and carboxypeptidase trimming.

Project description:Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

Dataset Information

Altered ?-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer's Disease.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets