Stalled Amyloid-β Production as a Contributing Cause of Alzheimer's Disease
It took twenty years of work and enormous expenditure, but the most recent immunotherapies targeting amyloid-β are capable of clearing most of this form of amyloid from the brain. Unfortunately, this class of therapy produces very little gain for patients in the later stages of Alzheimer's disease. This may be because the amyloid cascade hypothesis should be interpreted to mean that amyloid-β plays no great role in the pathology of the later stages of Alzheimer's disease, it only sets the stage for neuroinflammation and tau aggregation, and it is those mechanisms that destroy the brain and kill patients. It remains to be seen as to whether these therapies can produce even modest gains in the early stages of the condition, acting in a more preventative mode to stop the development of later pathology.
The poor results for technically successful immunotherapies are spurring a greater interest in alternative mechanisms in the research community, continuing the trend started by frustration with the slow progress towards effective amyloid clearance. There are many programs, hypotheses, and mechanistic targets in search of support for the development of potential new therapies. They tend to keep a focus on the known molecular biochemistry surrounding amyloid-β, but bring new interpretations to the table. Today's research materials are an example of the type, reintepreting the role of γ-secretase in the production of amyloid-β as a crucial part of disease progression. As with all of the other novel ideas, the only real way to determine the importance of this mechanism is to build therapies and try them in patients. The mouse models of Alzheimer's disease have historically told us little about whether any given mechanism is actually important in our own species.
Study suggests stalled amyloid protein production drives Alzheimer's disease
For several decades, researchers studying Alzheimer's disease have been working to understand the 'amyloid cascade hypothesis', which proposes that a buildup of amyloid-β (Aβ) proteins kickstarts a cascade of events that leads to neurodegeneration and dementia. Despite advances in understanding the mutations that lead to Aβ aggregation, uncertainties about the assembly of neurotoxic Aβ proteins remain. 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). Researchers 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. 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. Researchers have now further assessed mutations in γ-secretase, showing that they 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. 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. We propose that γ-secretase activators that can rescue stalled proteolysis could complement treatments targeting other Alzheimer's-associated pathways."