FEATURE ARTICLE
Alzheimer's Disease
The molecular origins of the disease are coming to light, suggesting several novel therapies
Vernon Ingram
What Is Alzheimer's Disease?
The first description of Alzheimer's disease appeared about 100 years ago, published by the neurologist Alois Alzheimer in Munich. He described the case of a 51-year-old woman with memory deficits and striking behavioral changes. Her symptoms worsened quite rapidly, and as the condition progressed she became unable to care for herself. After the woman's death five years later, an autopsy revealed extensive pathological changes: The cortex was shrunken, and there were many small, abnormal structures scattered throughout the brain. Using a silver tissue stain to visualize the structures, Alzheimer noted a profusion of extracellular senile plaques (normally found in the elderly) and never-before-seen tangles inside neurons. These tangles appeared to be made of long, knotted filaments, or fibrils, under the microscope. On the basis of these novel fibrillar tangles, plus the patient's age and the unusual number of senile plaques, Alzheimer distinguished this disease from "normal" senile dementia, a more benign and gradual age-related loss of mental function. In fact, for a long time Alzheimer's disease was referred to as pre-senile dementia, indicating that it occurred earlier than expected.
Alois Alzheimer noted that many of the characteristic changes in brain anatomy were concentrated in the cortex. For reasons that are still incompletely understood, some brain regions (including frontal cortex) are especially susceptible to the cellular trauma of Alzheimer's disease. This localized damage leads to a stereotyped order of decline in specific brain functions. Smell is one of the first to disappear, followed by memory, orientation and behavioral grooming, self-preservation functions. On the other hand, locomotion stays intact, distinguishing the disease from Parkinson's disease.
What actually goes wrong in the brain of an Alzheimer's patient? There are some half-dozen different genetic circumstances that can trigger the disease, and probably others that are currently unknown. They all lead to the same molecular pathology—the formation of aggregates of a "misfolded" fragment of a normal protein. This normal protein, the amyloid precursor protein or APP, is embedded in the outer membrane of cells in a variety of tissues. In the course of its normal function, APP is cut into segments, or peptides, at three specific sites targeted by α-, β-, and γ-secretase enzymes, respectively. During the development of Alzheimer's disease, the APP protein is cut at the β and γ sites, resulting in a fragment that folds itself into a sticky, self-aggregating shape. This peptide can be from 39 to 43 amino acids long, owing to a peculiar variability in the β-secretase cleavage site. Not all of the versions are produced in equal amounts—the so-called Aβ1—40 is most common—and some forms are worse than others, with the most toxic peptide being Aβ1-42. This fragment includes the first 42 amino acids after the β-secretase site and readily forms insoluble clumps in the brain. These aggregates are toxic and lead aggressively to the dysfunction of nearby brain cells and their consequent death and removal. Once these brain cells are gone, there is at present no way to replace them.
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