amyloid precursor protein

Researchers discover novel function of protein linked to Alzheimer's disease

A research team led by the National Neuroscience Institute (NNI) has uncovered a novel function of the Amyloid Precursor Protein (APP), one of the main pathogenic culprits of Alzheimer’s disease. This discovery may help researchers understand how the protein goes awry in the brains of Alzheimer’s disease patients, and potentially paves the way for the development of innovative therapeutics to improve the brain function of dementia patients.

The findings were published in the prestigious scientific research journal Nature Communications last month. The study, which is led by Dr Zeng Li and her team from NNI, involved investigators from Duke-NUS Graduate Medical School and the Agency for Science and Technology (A*STAR).

Alzheimer’s disease is the most common form of dementia, which is set to rise significantly from the current 28,000 cases to 80,000 cases in 2030 among Singaporeans aged 60 and above. With a rapidly aging population, the burden of the disease will be profound affecting not just the person afflicted, but also the caregiver and family. While the exact cause of Alzheimer’s disease remains unknown, one of its pathological hallmarks is clear – the clumping of APP product in the brain when the protein is abnormally processed.

Finding out more about APP can help researchers gain a better understanding of the disease, and potentially identify biomarkers and therapeutic targets for it. However up till this point, little was known about the APP’s primary function in the brain.

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A newly discovered molecular feedback process may protect the brain against Alzheimer’s

It is a hallmark of Alzheimer’s disease: Toxic protein fragments known as amyloid-β clumped together between neurons in a person’s brain. Neurons themselves make amyloid-β, and for reasons that aren’t fully understood, its accumulation ultimately contributes to the memory loss, personality changes, and other symptoms that patients with this degenerative disease often suffer from.

(Image caption: Ready to ship: Within cells displaying features of Alzheimer’s, the researchers found high concentrations of WAVE1 and the amyloid-β precursor protein within the Golgi, an organelle in which proteins are packaged for shipping. These appear in the cell above as bright, yellow clusters)

New research by Rockefeller University scientists and their colleagues have identified a series of naturally occurring molecular steps—known as a pathway—that can dampen the production of amyloid-β. These results, reported in Nature Medicine on August 17, suggest a new route in the search for Alzheimer’s therapies.

“Our discovery centers on a protein called WAVE1, which we found to be important in the production of amyloid-β. The reduction of WAVE1 appears to have a protective effect against the disease,” says study author Paul Greengard, Vincent Astor Professor, head of the Laboratory of Molecular and Cellular Neuroscience, and director of The Fisher Center for Alzheimer’s Research. “When levels of amyloid-β rise, there is an accompanying increase in another molecule, AICD, which reduces the expression of WAVE1. This has the effect of reducing the production of amyloid-β.

“By targeting steps within this newly discovered pathway,” he adds, “it may be possible to develop drugs to reduce amyloid-β that potentially could be used to either treat or prevent Alzheimer’s disease.”

WAVE1 is known to help to build filaments of a protein called actin that serve as basic components of cellular structures. In the current study, the team, including first author Ilaria Ceglia, who conducted this work while a research associate in the lab, examined the levels of WAVE1 in mouse and cellular models of Alzheimer’s disease and found that they were unusually low. Research done by a collaborator at Columbia University found this was also true for the brains of human patients with the disease.

To take a closer look at the relationship between amyloid-β and WAVE1, the researchers tested the brains and memories of mice genetically altered to produce high levels of amyloid-β and varying levels of WAVE1. They found a dose-dependent response: Mice brains with low WAVE1 levels produced less amyloid-β, and these animals performed better on memory tests.

Next, the researchers wanted to know how WAVE1 affects the production of amyloid-β. The precursor to this Alzheimer’s protein is not harmful by itself, and does not normally yield brain-damaging products. However, sometimes the precursor is processed in such a way that it produces disease-promoting amyloid-β.

The team found high levels of both the amyloid precursor protein and WAVE1 in a compartment within the cell known as the Golgi, which acts as a sort of shipping department. Here proteins are packaged before they are sent out to various destinations within the cell. In the case of the amyloid precursor protein, the first destination is the cell’s outer membrane. From there, it travels into the compartments within the cell, where it is processed to produce amyloid-β.

Because the formation of structural filaments is critical to the process by which cargo buds off and leaves the Golgi, the researchers suspected a role for WAVE1. Their experiments showed an interaction between WAVE1 and the amyloid precursor protein, and confirmed that WAVE1 mediates the formation of cargo vesicles containing amyloid precursor protein.

“The result is a negative feedback loop,” says corresponding author Yong Kim, a research assistant professor in the lab. “More amyloid-β means more AICD. Our experiments reveal that AICD travels into the nucleus where it reduces the expression of WAVE1. Less WAVE1 means less precursor protein in cargo traveling to the membrane for conversion into amyloid-β. In Alzheimer’s disease, this negative feedback appears to lose its protective effect, and the next step for us is to figure out how.”

Rescuing the Golgi Puts Brakes on Alzheimer’s Progress

Alzheimer’s disease (AD) progresses inside the brain in a rising storm of cellular chaos as deposits of the toxic protein, amyloid-beta (Aβ), overwhelm neurons. An apparent side effect of accumulating Aβ in neurons is the fragmentation of the Golgi apparatus, the part of the cell involved in packaging and sorting protein cargo including the precursor of Aβ. But is the destruction the Golgi a kind of collateral damage from the Aβ storm or is the loss of Golgi function itself part of the driving force behind Alzheimer’s? This was the question for Yanzhuang Wang, Gunjan Joshi, and colleagues at the University of Michigan, Ann Arbor, as they set out to uncover the mechanism damaging the Golgi, using a transgenic mouse and tissue culture models of AD to look at what was going on.

The unsurprising part of the answer was that rising levels of Aβ do lead directly to Golgi fragmentation by activating a cell cycle kinase, cdk5. The surprising part of the answer was that Golgi function can be rescued by blocking cdk5 or shielding its downstream target protein in the Golgi, GRASP65. The even more surprising answer was that rescuing the Golgi reduced Aβ accumulation significantly, apparently by re-opening a normal protein degradation pathway for the amyloid precursor protein (APP). To Wang et al, this suggested an entirely new line of attack for drugs hoping to slow AD progression.

Speaking at the ASCB/IFCB Meeting in Philadelphia, the researchers now say that Golgi fragmentation is in itself a major—and until now an unrecognized—mechanism through which Aβ extends its toxic effects. They believe that as Aβ accumulation rises, damage to the Golgi increases, which in turn accelerates APP trafficking, which in turn increases Aβ production. This is a classic “deleterious feedback circuit,” they say. By blocking cdk5 or its downstream target, that circuit can be broken or greatly slowed. “Our study provides a molecular mechanism for Golgi fragmentation and its effects on APP trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment,” the Michigan researchers report.