The prevailing view of Alzheimer's disease continues to be the amyloid cascade hypothesis, that a slow age-related accumulation of misfolded amyloid-β causes sufficient dysfunction to set the stage for later pathology involving senescent cells, chronic inflammation, and aggregation of altered tau protein. That later pathology is much more destructive, self-sustaining enough for removal of amyloid-β, now successfully achieved in a number of immunotherapy clinical trials, to be of little use to patients.
It remains that case that the research community sees removal of amyloid-β as a potential way to prevent the development of Alzheimer's disease, assuming sufficiently early and sustained intervention to maintain low levels of amyloid-β aggregation throughout life. Today's open access paper discusses an immunization approach: direct the immune system to destroy excess amyloid-β by provoking it into recognizing a part of the amyloid-β protein as foreign.
The interesting unresolved question continues to be why amyloid-β aggregation is an age-related process. A growing faction within the research community question whether amyloid-β accumulation is actually an important contributing cause of Alzheimer's disease, versus being a side-effect of other, more relevant processes. For example, amyloid-β is an anti-microbial peptide, a component of the innate immune system, and it may be that increased levels of amyloid-β are a feature of persistent vital infection that drives chronic inflammation, where that inflammation is the true driving pathology.
Researchers have discovered a possible new approach to immunization against Alzheimer's disease (AD). Their method uses a recombinant methionine (Met)-rich protein derived from corn that was then oxidized in vitro to produce the antigen: methionine sulfoxide (MetO)-rich protein. This antigen, when injected to the body, goads the immune system into producing antibodies against the MetO component of beta-amyloid, a protein that is toxic to brain cells and seen as a hallmark of Alzheimer's disease.
"As we age, we have more oxidative stress, and then beta-amyloid and other proteins accumulate and become oxidized and aggregated - these proteins are resistant to degradation or removal. In a previous 2011 published study, I injected mouse models of Alzheimer's disease with a similar methionine sulfoxide-rich protein and showed about 30% reduction of amyloid plaque burden in the hippocampus, the main region where damage from Alzheimer's disease occurs."
The MetO-rich protein used for the vaccination of AD-model mice is able to prompt the immune system to produce antibodies against MetO-containing proteins, including MetO-harboring beta-amyloid. The introduction of the corn-based MetO-rich protein (antigen) fosters the body's immune system to produce and deploy the antibodies against MetO to previously tolerated MetO-containing proteins (including MetO-beta-amyloid), and ultimately reduce the levels of toxic forms of beta-amyloid and other possible proteins in brain.
The brain during Alzheimer's disease (AD) is under severe oxidative attack by reactive oxygen species that may lead to methionine oxidation. Oxidation of the sole methionine of beta-amyloid (Aβ), and possibly methionine residues of other extracellular proteins, may be one of the earliest events contributing to the toxicity of Aβ and other proteins in vivo. In the current study, we immunized transgenic AD (APP/PS1) mice at 4 months of age with a recombinant methionine sulfoxide (MetO)-rich protein from Zea mays (antigen). This treatment induced the production of anti-MetO antibody in blood-plasma that exhibits a significant titer up to at least 10 months of age.
Compared to the control mice, the antigen-injected mice exhibited the following significant phenotypes at 10 months of age: better short and long memory capabilities; reduced Aβ levels in both blood-plasma and brain; reduced Aβ burden and MetO accumulations in astrocytes in hippocampal and cortical regions; reduced levels of activated microglia; and elevated antioxidant capabilities (through enhanced nuclear localization of the transcription factor Nrf2) in the same brain regions.