Researchers from a leading US biotech company have discovered a new route through which Alzheimer’s disease may either trigger or maintain the destruction of brain cells: the mechanism that it hijacks is normally used to prune unwanted brain cells in early development and involves a hitherto unsuspected part of a known culprit, APP, the precursor of the amyloid plaques found in the brains of people with Alzheimer’s disease.
The researchers are part of a team of scientists at Genentech Inc, and they have published their findings in the February 19 advanced online issue of the journal Nature.
Co-author Marc Tessier-Lavigne, who is executive vice president of research drug discovery at the company said in a web interview:
“In the field of Alzheimer’s disease, it is well known that a bad actor in the brain is a protein called APP, and what we found is a new twist on our understanding of what APP does.”
“APP is a large protein that sits in the cell membrane”, said Tessier-Lavigne, who explained that for many years research on Alzheimer’s had focused on a section of the protein called Abeta.
“It’s been argued that Abeta is toxic and contributes to the degeneration that occurs in the disease,” he explained .
But what he and his team found almost by mistake was that a different part of APP, which they call N-APP, may also be involved. N-APP can trigger neuron death and degeneration, “we’ve figured out how it is that it triggers that degeneration”, said Tessier-Lavigne, and that is the subject of the paper they have published.
“We believe that this could be involved in either the initiating or helping the progression of Alzheimer’s disease,” he added.
In their background information the authors explain that scientists have already discovered there are natural mechanisms through which unwanted axons and neurons are pruned and killed to help “sculpt neuronal connections during development”, but exactly how they do this is still somewhat of a mystery.
In this study the researchers discovered that beta-amyloid precursor protein (APP) and death receptor 6 (DR6, also known as TNFRSF21) trigger a widespread self destruction program that relies on caspases (sometimes called “executioner proteins” because of the role they play in apoptosis or programmed cell death).
DR6 is a receptor expressed by developing neurons and is used in normal cell death and pruning of axons (the fibre that carries the eletrical signal from the neuron). The researchers were working on something else and came across DR6 and they wondered what triggered it. That is what started them down this route.
What they discovered was that while caspase 3 is involved in cell death of the neuron body, it is caspase 6 that is required for axon degeneration and this is triggered when a relatively unknown part of APP (N-APP, a cleaved amino-terminal fragment of APP) binds to DR6.
They concluded that:
“Our results indicate that APP and DR6 are components of a neuronal self-destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase 6, contributes to Alzheimer’s disease.”
The study relied on in vitro (lab cultures) and in vivo (using mutant mouse models) tests, which means clinical applications are still some years off. However, Tessier-Lavigne is confident that the discovery offers new targets for therapy development.
“We can try to prevent the initiation or progression of the disease by blocking the portion of the APP molecule that we’ve identified or some of the other downstream signaling mechanisms that we’ve pinpointed as well.”
“It provides us with a whole host of new entry points to try to block or mitigate the effects of the disease,” he added.
“APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.”
Anatoly Nikolaev, Todd McLaughlin, Dennis D. M. O’Leary and Marc Tessier-Lavigne.
Nature 457, 981-989 (19 February 2009)
doi:10.1038/nature07767
Sources: Journal abstract, Genentech.
Written by: Catharine Paddock, PhD