Evidence map›Paper›PMID 40671818›Full record

ArticleResearch square2025

Lysosomal Protease-Mediated APP Degradation is pH-Dependent, Mutation-Sensitive, and Facilitates Tau Proteolysis.

Caroline Ackley, Zoe Liau, Shruti Arya, Tara Antee, Giselle M Knudsen, Courtney Lane-Donovan, Paul J Sampognaro, Aimee W Kao

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

8 authors.

Caroline AckleyMemory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190, California, USA.
Zoe LiauMemory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190, California, USA.
Shruti AryaMemory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190, California, USA.
Tara AnteeMemory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190, California, USA.
Giselle M KnudsenAlaunus Biosciences, Inc., South San Francisco, 94080, California, USA.
Courtney Lane-DonovanMemory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190, California, USA.
Paul J SampognaroMemory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190, California, USA.
Aimee W KaoMemory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, 100190, California, USA.

Funding

Tau Metabolism in FTD: From Gene Mutations to Molecular Chaperones and Lysosomal ProteasesU54NS123985 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KARCH, CELESTE MARIE · 2021 to 2025
$9.0M
Systematic profiling of lysosomes with age to improve proteostasis in Alzheimer'sR01AG057342 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KAO, AIMEE · 2018 to 2022
$3.8M
TDP43 Degradation by the Lysosomal Proteases in Amyotrophic Lateral SclerosisK08NS121519 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Paul Joseph Sampognaro · 2022 to 2026
$1.1M
Illuminating Lysosomal Dysfunction in Aging and Alzheimer's Disease (AD)K08AG083050 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Courtney E Lane-Donovan · 2023 to 2026
$712k
NIA NIH HHS K08 AG083050NIA NIH HHS R01 AG057342NINDS NIH HHS K08 NS121519NINDS NIH HHS U54 NS123985
6 · The paper itself

Abstract

Background: The accumulation and aggregation of amyloid beta (A Methods: We applied Multiplexed Substrate Profiling by Mass Spectrometry (MSP-MS) to map cleavage sites within APP that may be targeted by lysosomal proteases, also known as cathepsins. We then employed cell-based and Results: Our findings confirm that APP is enriched in the endolysosomal compartment, where it is processed by many, but not all, cathepsins. Our experiments reveal that cleavages at several mapped APP sites are sensitive to both changes in pH and the presence of pathogenic variants E693G and E693Q. Additionally, we discovered that the large soluble domain of APP (sAPP) enhances tau cleavage by cathepsin G Conclusions: Collectively, these results underscore the importance of lysosomal processing of APP, identify a link between APP and tau, and suggest new avenues for exploring AD pathogenesis. They also point to potential therapeutic targets related to the lysosomal function of APP and its impact on neurodegenerative disease.

Indexed as

Alzheimer’s diseaseamyloid-betaamyloid-precursor proteinAPPautophagyAβcathepsinlysosomeneurodegenerationproteasetau

Identifiers

PMID40671818
PMCPMC12265180

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.