What, exactly, is the trigger for Alzheimer’s disease? Is there one such thing? At today’s annual meeting of the American Society for Biochemistry and Molecular Biology in Boston, Li Huei Tsai of Harvard Medical School presented data suggesting that the protein p35 may just fit the bill. Though p35 is a relatively short-lived protein (see ARF related news story), it can shoot a fragment of itself, p25, into neuronal cytosols. If p35 is a trigger, then p25 is a bullet. Being much more stable than its parent, p25 lodges like a piece of lead in the brain where it leads to chronic activation of the protein kinase Cdk5. This kinase phosphorylates tau, the major constituent of neurofibrillary tangles, and in keeping with this function, overexpression of p25 has been shown to cause accumulation of tangles and neuronal apoptosis (see ARF related news story).
Now Tsai shows that excess p25 can also accelerate the production of amyloid-β and formation of plaques, thus linking the three major pathological signatures of AD—amyloid-β plaques, and neurofibrillary tangles—and neuronal death.
Tsai has raised mice that express p25 driven by a promoter that can be shut off by the antibiotic doxycycline. Removing this safety valve leads to overexpression of p25 in the brain. When Tsai allowed these animals to mature to adulthood and then removed the antibiotic from their diets, the results were profound. The mice developed all the hallmarks of AD, including elevation of the Aβ42 peptide that triggers the development of plaques. Since p25 accumulates in the brains of people with AD (see ARF related news story), these results suggest that cleavage of p35 may be a trigger for the disease. It is also worth noting that p25 has been shown to accumulate following stroke (see ARF related news story). Among the current hypotheses for how the pathology of Alzheimer’s begins is that hypoperfusion, or mini strokes, may be key (see ARF Live Discussion on vascular factors in AD).—Tom Fagan.
- Enzyme Essential to Brain Development Found to Hyperphosphorylate Tau, Kill Neurons
- Aiding and Abetting, Hyperactive CDK5 Gives Mouse Tangles
- Tau Kinase Mediates Stroke Damage
No Available Further Reading