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An immune-based therapy against Alzheimer's disease (AD) not only removes the protein that causes the brain-clogging plaques in the disease, researchers have found. They have discovered that the treatment also unleashes the cell's protein garbage disposal system to rid brain cells of the protein tangles that are the other hallmark of the disease.
Thus, said researchers led by Frank LaFerla, immune therapy against AD offers the promise of a broad assault on the disease.
In their experiments, the researchers analyzed the effects of injecting antibodies against the culprit protein, called Ab peptide, that makes up the toxic amyloid plaque into mouse strains that show Alzheimer's pathology. Such immunization consists of administering antibodies that specifically target the protein for destruction by the body's immune system.
The researchers found that the Ab antibodies cleared the Ab peptide not only outside brain cells, but also inside--the first time such "intracellular" clearance has been shown.
Importantly, they also found that treatment with Ab antibodies resulted in an effective clearance of the different protein, called tau, that makes up the "neurofibrillary tangles" inside brain cells that kill the cells in AD. The researchers found that Ab clearance occurred before tau clearance, suggesting a causative role of the former. Also, they found that when immune therapy was discontinued the tau pathology reemerged after Ab pathology.
"Taken together, these data provide compelling evidence for the amyloid cascade hypothesis that Ab lies upstream of tau in the neurodegenerative cascade leading to AD and further suggest that Ab-based therapeutic approaches may be efficacious in removing both hallmark lesions," wrote the researchers.
The deadly tangles are created when the tau protein becomes "hyperphosphorylated," so the researchers tested whether its clearance after injection of Ab antibodies depended on the tau protein's phosphorylation stage. They found that the later, hyperphosphorylated tau was resistant to clearance.
The researchers said that their results "indicate that Ab immunization may be useful for clearing both hallmark lesions of AD, provided that intervention occurs early in the disease course."
LaFerla and his colleagues showed that immune therapy against Ab clears the seemingly unrelated tau protein by alleviating the interference that the mass amounts of Ab peptide apparently causes in the cell's protein garbage disposal, the proteasome. This large complex of proteins detects and shreds proteins that are faulty or no longer needed by the cell. When the researchers used drugs to inhibit the proteasome in the mice given the immune treatment, they found that the Ab still cleared from the mouse brains, but the clearance of tau was inhibited.
To show that it was the clearance of Ab that alleviated the pathologies of AD, the researchers gave the mice a drug that inhibited an enzyme that is key to producing Ab. They found that blocking Ab production also led to the clearance of tau.
The researchers concluded that "The most clinically relevant finding is that using anti-Ab-based therapeutic approaches can clear the tau burden." However, they wrote, since tau becomes resistant once the protein becomes hyperphosphorylated, administering immunotherapy late during the disease "may still clear amyloid plaque, although it will be insufficient to impact the neurofibrillary pathology."
The researchers suggested that a combination treatment that includes additional antibodies against the resistant tau might be useful. "These findings raise the intriguing possibility that a multi-antibody approach (i.e., one targeted against Ab and one against tau) may provide the most significant clinical benefit for the treatment of AD," they wrote.
The findings of clearance of Ab inside the cell by immune therapy may also have implications for treating the muscle disease inclusion body myositis, said the researchers. In this disorder, accumulation of Ab in muscle cells leads to muscle degeneration.
Salvatore Oddo, Lauren Billings, J. Patrick Kesslak, David H. Cribbs, and Frank M. LaFerla: "Ab Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome"
Published in Neuron, Volume 43, Number 3, August 5, 2004, pages 321-332.
Journal
Neuron