Amyloid beta and tau are the two proteins most closely associated with Alzheimers disease, and understanding exactly how they interact has been one of the central challenges in neurodegeneration research. Alzheimers affects approximately 40 million people worldwide, and there are currently no treatments capable of stopping or reversing its progression. Researchers at the University of Cambridge have now identified a previously unknown pathway connecting amyloid beta to tau inside human neurons, a finding that opens new possibilities for drug development and was published in Cell Reports.
What the Amyloid Beta and Tau Protein Pathway Research Found
The study focused on how a protein called amyloid precursor protein, or APP, is broken down into toxic fragments of amyloid beta and how that process influences the behavior of tau. It has been known for some time that amyloid beta builds up outside neurons to form plaques, and that this extracellular accumulation can trigger increased production of tau. The Cambridge research identified a second, distinct pathway operating entirely within the cell itself.
When secretase enzymes break down APP inside the neuron, the resulting amyloid beta fragments alter tau levels without ever leaving the cell. As lead researcher Dr. Rick Livesey of the Wellcome Trust and Cancer Research UK Gurdon Institute explained, the cell essentially does it to itself. This intracellular pathway had not been previously identified, and its discovery means that targeting amyloid beta outside the cell, which has been the primary strategy in most Alzheimers drug trials to date, may be addressing only part of the problem.
Why Human Neurons Were Essential for Finding This Amyloid Beta Pathway
One of the most significant methodological contributions of this study is what it reveals about the limitations of mouse models in Alzheimers research. Mice do not naturally develop Alzheimers disease and do not respond to the secretase inhibiting drugs used in this study the way human neurons do. The pathway connecting amyloid beta to intracellular tau changes simply could not have been identified in an animal model.
To work with genuine human neurons, the Cambridge team used skin cells from individuals with the familial form of Alzheimers, the rare inherited version that typically causes onset in the thirties or forties and accounts for one to five percent of all cases. These skin cells were reprogrammed into induced pluripotent stem cells and then directed to become neurons carrying all the molecular characteristics of Alzheimers disease. These clusters of human neurons, described by the researchers as mini brains, provided a biologically authentic system for observing how amyloid beta and tau interact under drug manipulation.
How Drug Manipulation of Amyloid Beta Levels Affects Tau
Using three classes of drugs that inhibit the secretase enzymes responsible for breaking APP into amyloid beta, the researchers were able to increase or decrease the rate of APP processing. By doing so, they could directly observe corresponding changes in tau levels within the neurons. When amyloid beta production increased, tau levels rose. When it was suppressed, tau levels fell.
This direct, manipulable relationship between the rate of APP breakdown and tau levels confirms that the pathway is functionally real and pharmacologically accessible. The ability to alter tau by targeting the intracellular amyloid beta process represents a new potential therapeutic entry point that differs from all current drug strategies in Alzheimers research.
What This Means for Future Alzheimers Drug Development
Although the pathway was identified in neurons carrying the familial Alzheimers mutation, the researchers found that the same pathway exists in healthy human neurons as well. This finding suggests that targeting the same mechanism in late onset Alzheimers, the far more common form of the disease, may also be feasible. The pathway is not a quirk of the rare genetic variant but an intrinsic feature of how human neurons handle APP processing.
Dr. Simon Ridley, Head of Research at Alzheimers Research UK, described the findings as meaningfully advancing understanding of the molecular changes that cause dementia and expressed commitment to funding further research to test drugs that halt disease progression through this newly identified mechanism.
To read more about Alzheimers and neurodegenerative disease research, visit the FOMAT blog. FOMAT conducts Alzheimers and CNS clinical trials at sites across the United States. To learn more about active studies, visit FOMAT’s patient studies page.
For the full source, see the original article at University of Cambridge.