FEATURE ARTICLE
Alzheimer's Disease
The molecular origins of the disease are coming to light, suggesting several novel therapies
Vernon Ingram
The Molecular Origin of the Disease
Senile plaques from postmortem Alzheimer's brains are largely composed of short amyloid peptides, as shown in 1984 by George Glenner and his colleagues at the University of California, San Diego. Identification of the amyloid peptide, originally described as "beta protein" because of its adoption of a beta-sheet conformation, soon led to the cloning of the APP gene. The relationship of toxic amyloid fragments to benign full-length APP points to an enduring question in the field: How is the poisonous peptide produced?
In normal or young brains, the full-length membrane-spanning protein is broken down into functional fragments, including a large cytoplasmic piece used to regulate important cell mechanisms. But in Alzheimer's brains, degradation of APP takes a wrong turn. For reasons that are still not entirely clear, the relative activities of the three proteases, or protein-cutting enzymes, that cleave APP change dramatically. Dennis Selkoe at Harvard's Brigham and Women's Hospital, among others, showed that two of them, the β- and γ-secretases, become much more active, resulting in overproduction of the 42–amino acid peptide. Meanwhile, the α-secretase, which acts at a location between them, becomes relatively inactive. This is unfortunate, because cutting the precursor protein at the α site produces harmless fragments.
The newly cleaved Aβ1-42 peptide is immediately exported. This unique feature distinguishes Alzheimer's disease from most other neurodegenerative diseases, which act inside cells. It also simplifies potential therapies, since the helpful "drug"—an antibody, peptide or other molecule—does not have to enter a cell, where it might cause unwanted effects.
Once outside the cell, Aβ1-42 assumes a beta-sheet-containing, aggregate-prone conformation. In cell culture, the aggregated peptides cause neurons to die, and the same is true when they are injected into the mammalian brain. This cell death can occur by apoptosis (programmed cell death) or by necrosis. The former involves cell shrinking, membrane destabilization (blebbing), and DNA degradation before garbage-eating macrophage cells clean up the imploded remains. Necrosis is less tidy. Here the cell swells and explodes, releasing a witches' brew of compounds that cause the inflammation characteristic of Alzheimer's disease. The importance of blocking the products of necrosis has been emphasized recently with the finding that some anti-inflammatory medications may delay disease onset and progression.
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