Altered γ-Secretase Processing of APP Disrupts Lysosome and Autophagosome Function in Monogenic Alzheimer’s Disease.
Open accessAbstract
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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L685,458 boosts APP-βCTF levels by inhibiting its cleavage.
“which boosts APP-CTF levels by inhibiting its cleavage (Fig. 5 A, B) (Jiang et al., 2010;Lauritzen et al., 2016;Hung and Livesey, 2018).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Hung and Livesey, 2018
The Results section (‘Gamma-Secretase Inhibition Disrupts Function of the Lysosomal-Autophagic System in Human Neurons’; page not provided) reports that inhibiting γ-secretase prevents β-CTF turnover and markedly increases β-CTF levels. But the Methods name DAPT as the γ-secretase inhibitor used, not L685,458, so this paper does not establish the claim for that specific compound. (LLM, conf=0.89)
Experimental — accuracy not yet measuredEndosomal anomalies in DS are APP-dependent and mediated by APP-βCTF.
“Lysosomal deficits in DS add to the known endosomal anomalies known to develop in DS within the same vesicular trafficking pathway, which include some signature features of early AD and are also APP-dependent and mediated by APP-CTF (Jiang et al., 2010(Jiang et al., , 2016;;Hung and Livesey, 2018).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Hung and Livesey, 2018
In the Results section on early endosomes (page unavailable), the paper reports enlarged early endosomes in trisomy 21 (DS) neurons, alongside neurons with APP duplication or mutation. That supports the presence of endosomal anomalies and an association with APP, but does not establish that the DS endosomal anomalies are APP-dependent or mediated by APP-βCTF. Its β-secretase inhibition and APP-knockout results address lysosomal-autophagy defects, not the early-endosome anomalies. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe reduction in amyloid beta production by NB-360 in oligodendrocytes is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors.
“Notably, this reduction in Aβ production is similar to what has previously been shown in human iPSC-derived neurons upon administration of NB-360 or similar BACE inhibitors [21–24]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [21]
Increased APP-βCTF has been linked to lysosomal degradation defect in neurons derived from individuals with DS (Ts21) or familial AD with APP mutation.
“Increased APP-CTF has been linked to lysosomal degradation defect seen in the neurons derived from individuals with DS (Ts21) or familial AD with APP mutation (Hung and Livesey, 2018).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Hung and Livesey, 2018
APP-βCTF has been previously linked to lysosomal dysfunction in AD models involving overexpressed forms of FAD-mutated APP with or without additional overexpression of other mutated human AD genes, and in iPSC generated Ts21 neurons.
“APP-CTF has also been previously linked to lysosomal dysfunction in AD models involving overexpressed forms of FAD-mutated APP with or without additional overexpression of other mutated human AD genes (Lauritzen et al., 2012(Lauritzen et al., , 2016;;Yang et al., 2014;Kaur et al., 2017;Bourgeois et al., 2018), and in iPSC generated Ts21 neurons (Hung and Livesey, 2018).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Hung and Livesey, 2018
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References 55 · Cited by 159
- Authors
- Hung, C. O. Y., & Livesey, F. J.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Livesey, Frederick J.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 25
- Issue
- 13
- Pages
- 3647-3660.e2
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6315085
- OpenAlex
- W2906336433
- Cited by
- 159
- References
- 55
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 16 · 2023: 20 · 2022: 28 · 2021: 20 · 2020: 26 · 2019: 13
- FWCI
- 10.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (WT101052MA)
- Cancer Research UK
- Gurdon Institute
- Alborada Trust
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- APP, presenilin 1, gamma-secretase, BACE1, lysosomal function, autophagy, autophagosome clearance, lysosomal proteolysis, neuronal dysfunction, CRISPR knockout
- MeSH terms
- Autophagosomes, Alzheimer Disease, Autophagy, Axons, Cerebral Cortex, Humans, Lysosomes, Mutation, Protein Processing, Post-Translational, Endosomes, Amyloid beta-Protein Precursor, Presenilin-1, Amyloid Precursor Protein Secretases, Proteolysis, CRISPR-Cas Systems
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