Breakthrough Study Reveals How Protein Glitches May Be Driving Alzheimer’s

For years, scientists have focused on amyloid beta buildup as the main culprit in Alzheimer’s disease, but a new study suggests the real problem might lie in a stalled protein-cutting process in the brain.

Researchers found that mutations in the PSEN1 gene disrupt how the γ-secretase enzyme trims amyloid precursor protein (APP), leading to the accumulation of harmful intermediates. This discovery shifts the spotlight from amyloid beta to the enzyme’s failure to properly process APP, opening new doors for treatment strategies that could restore this disrupted process.

New Insights into Alzheimer’s Origins

According to a new study, Alzheimer’s disease is likely caused by stalled protein processing in the brain.

The research, published as a Reviewed Preprint in eLife, explores how mutations in the presenilin-1 (PSEN1) gene interfere with the processing of amyloid precursor protein (APP). Normally, APP is broken down into amyloid beta (Aβ) protein, which can accumulate in the brains of people with Alzheimer’s. The study provides strong evidence and detailed analysis supporting this connection, and its findings could help in the development of new Alzheimer’s treatments.

Examining the Amyloid Cascade Hypothesis

For years, scientists have studied the amyloid cascade hypothesis, which suggests that a buildup of Aβ proteins triggers a series of harmful events leading to neurodegeneration and dementia. However, this new research shifts the focus toward problems in the protein processing system itself, offering a fresh perspective on the disease’s root causes.
“Despite advances in understanding the mutations that lead to Aβ aggregation, uncertainties about the assembly of neurotoxic Aβ proteins remain,” says lead author Parnian Arafi, Medicinal Chemistry Research Assistant at the University of Kansas, US. “Moreover, clinical trials of treatments targeting Aβ protein or its aggregates have only been modestly effective, prompting a re-evaluation of Aβ as the primary driver of the Alzheimer’s disease process.”

Increasing focus is now being placed on the production of Aβ – a process called proteolysis, during which a precursor protein called amyloid precursor protein (APP) is trimmed by an enzyme called gamma-secretase (γ-secretase).

Mutations and Their Impact on APP Processing

Senior author Michael Wolfe, the Mathias P. Mertes Professor of Medicinal Chemistry, University of Kansas, and colleagues have previously shown that mutations found in early-onset familial Alzheimer’s disease (FAD) prevent γ-secretase from trimming APP effectively, leading to a build-up of lengthy forms of APP/Aβ intermediates. Moreover, in a worm model of FAD, they showed that these stalled γ-secretase-APP complexes lead to neurodegeneration, even when Aβ is not present.

In the current study, the team expanded their analysis to a further six mutations found in early onset FAD, measuring the impact of each mutation on every step in Aβ production. These are mutations that are being explored by the Dominantly Inherited Alzheimer Network (DIAN), because they cause Alzheimer’s disease to develop in people aged between 27 and 58 years old.

How Mutations Disrupt the γ-Secretase Process

To explore the effect of the mutations, they generated and purified mutant γ-secretase proteins and then incubated these with an APP fragment. This allowed them to determine how the mutant γ-secretase trimmed APP, by measuring the resulting protein fragments using a technique called mass spectrometry. They found that all the tested γ-secretase mutations caused deficiencies in multiple APP processing steps, the nature of which varied depending on the specific mutation. . By measuring the different products generated by each mutation, the team could quantitatively reveal how each specifically affects the production of different APP/Aβ intermediate proteins.

Stalled Proteolysis and Its Connection to Neurodegeneration

During proteolysis, the γ-secretase enzyme binds together in a complex initially with APP and then with subsequent intermediate forms of the protein as it is trimmed. To test the effects of FAD mutations on the stability of these enzyme-substrate complexes, the team used a pair of fluorescently labelled antibodies targeting the APP fragment and the enzyme – a reduction in the amount of fluorescence indicates when the enzyme and substrate are in proximity, that is, bound together.

For all of the mutants tested, the fluorescent signal was reduced compared to the normal functional enzyme, indicating that these mutations increase the stability of enzyme-substrate complexes. This result makes sense alongside initial proteolysis analysis, which suggests the proteolytic process had stalled.

“We’ve shown that these mutations lead to stalled proteolysis and stabilize the enzyme with its substrate in an intermediate form,” says Arafi. “These findings are in keeping with our ‘stalled complex’ hypothesis, where it is these enzyme-substrate complexes that trigger neurodegeneration even in the absence of amyloid beta-protein production.”

Implications for Future Alzheimer’s Treatments

“Difficulties in pinpointing the drivers of Alzheimer’s disease and in discovering effective therapeutics suggests that entities and processes beyond amyloid beta-protein might play pivotal roles in neurodegeneration,” says Wolfe. “By focusing on familial Alzheimer’s disease we have simplified the identification of pathogenic mechanisms, opening the door to developing new treatments. We propose that γ-secretase activators that can rescue stalled proteolysis could complement treatments targeting other Alzheimer’s-associated pathways.”

Reference: “Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production” by Parnian Arafi, Sujan Devkota, Emily Williams, Masato Maesako and Michael S Wolfe, 21 January 2025, eLife.
DOI: 10.7554/eLife.102274.2

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