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Alzheimer’s disease is a neurodegenerative disease characterized by aggregates of misfolded proteins such as amyloid-beta and tau in the brain. Previous research has attempted to use amyloid-beta vaccines to stall or reverse the progression of Alzherimer’s disease; however, these trials failed to produce a vaccine that was effective and safe00023-6/fulltext). A study released this week has identified a new target for Alzheimer’s disease vaccines that may succeed in clearing amyloid-beta plaques.
Amyloid-beta is a small, 36-43 amino acid protein that is cleaved from a larger amyloid precursor protein in the brain. After being cleaved, the small amyloid-beta protein can become misfolded, lose its function, and form oligomers, which are aggregate protein structures with many repeating identical units. Some of the amino acids on one end of the amyloid-beta structure fold over, creating a hairpin structure and contributing to plaque formation. Previous research has suggested the hairpin site is an effective target for preventing aggregation; however, no vaccine has yet been developed that exploits this molecular pattern.
The authors designed a peptide that is a portion of the amyloid-beta protein containing 14 amino acids that are cyclized to form a stable pseudo hairpin structure. They inoculated healthy mice with the cyclized peptide and measured the antibody response. Next, they immunized mice who exhibit Alzheimer’s-like dementia and measured the effect on amyloid-beta plaques in the brain. They also measured cognitive function and hippocampal volume, which both decline with Alzherimer’s disease.
The authors found that healthy mice had a robust immune response to immunization and produced antibodies specific to the pseudo hairpin protein they designed. In mice who develop Alheimer’s-like dementia, immunization significantly reduced the amount of amyloid-beta plaques in regions of the brain such as the cerebral cortex, hippocampus, and thalamus. These regions also exhibited increased glucose metabolism following immunization, indicating better metabolic health in the brain. Finally, immunization increased the number of neurons in the hippocampus, the brain region most associated with learning memory. Immunized mice with greater hippocampal volume performed better on learning and memory tasks.
Immunization with the novel pseudo hairpin structure reversed amyloid-beta aggregation in the brain and improved brain health and cognitive performance in mice. This exciting research may contribute to the development of Alzheimer’s disease vaccines in humans.
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