Background The accumulation and aggregation of amyloid beta (A<InlineEquation ID="IEq1"> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation>)—a peptide fragment derived from the proteolytic processing of amyloid precursor protein (APP)—is a central pathological feature of Alzheimer’s disease (AD) and a current target for disease-modifying therapies. Mutations in APP can also drive early-onset AD. While the roles of <InlineEquation ID="IEq2"> <EquationSource Format="TEX">$\alpha$</EquationSource> <EquationSource Format="MATHML"><math> <mi>α</mi> </math></EquationSource> </InlineEquation>-, <InlineEquation ID="IEq3"> <EquationSource Format="TEX">$\beta$</EquationSource> <EquationSource Format="MATHML"><math> <mi>β</mi> </math></EquationSource> </InlineEquation>-, and <InlineEquation ID="IEq4"> <EquationSource Format="TEX">$\gamma$</EquationSource> <EquationSource Format="MATHML"><math> <mi>γ</mi> </math></EquationSource> </InlineEquation>-secretases and their respective cleavage sites in APP processing are well characterized, much less is understood about the routine degradation of APP within sub-cellular compartments like the lysosome. 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 in vitro assays to examine the degradation of both wild-type and mutant APP by these enzymes. Results Our findings confirm that APP is enriched in the endo-lysosomal compartment, where it is processed by many 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 a specific cathepsin, CTSG, in vitro. 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 highlight potential therapeutic targets related to the lysosomal function of APP and its impact on neurodegenerative diseases.

Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis

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2026年1月19日

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

摘要

Background

The accumulation and aggregation of amyloid beta (A $\beta$ $β$ )—a peptide fragment derived from the proteolytic processing of amyloid precursor protein (APP)—is a central pathological feature of Alzheimer’s disease (AD) and a current target for disease-modifying therapies. Mutations in APP can also drive early-onset AD. While the roles of $\alpha$ $α$ -, $\beta$ $β$ -, and $\gamma$ $γ$ -secretases and their respective cleavage sites in APP processing are well characterized, much less is understood about the routine degradation of APP within sub-cellular compartments like the lysosome.

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 in vitro assays to examine the degradation of both wild-type and mutant APP by these enzymes.

Results

Our findings confirm that APP is enriched in the endo-lysosomal compartment, where it is processed by many 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 a specific cathepsin, CTSG, in vitro.

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 highlight potential therapeutic targets related to the lysosomal function of APP and its impact on neurodegenerative diseases.