FEATURE ARTICLE
Alzheimer's Disease
The molecular origins of the disease are coming to light, suggesting several novel therapies
Vernon Ingram
How Does Aβ1-42 Kill the Cell?
Recently we developed a molecular model to explain the neurotoxicity of the Aβ peptide. It accounts for the known importance of protein conformation and provides a direct link between extracellular toxicity and intracellular damage, dysfunction and death.
The key model feature is our observation of a selective association of aggregated Aβ peptide with specific neurotransmitter-gated ion channels in the cell membrane. These channels open in the presence of the neurotransmitter glutamate, but they also bind very specifically to an artificial glutamate analogue: α-amino-3-hydroxl-5-methyl-4-isoxazole-propionic acid, or AMPA. The specificity for AMPA distinguishes these channels from others that are also glutamate-regulated, and the AMPA-specific channels are the only ones affected by the Aβ peptide. In the presence of aggregated Aβ fragments—but not the soluble, nonaggregated fragments—the channels get stuck in an open position, allowing calcium ions to flood into the cell. This calcium influx disrupts cellular processes and eventually leads to cell death. In support of our hypothesis, there are reports that the AMPA channels affected in this way are restricted to the same specific areas of the brain that are involved in Alzheimer's disease.
Why is a large and lasting calcium ion influx so bad for a neuron? As it happens, Ca2+ is a vitally important signal used by dozens of systems within the cell. Local changes in cellular Ca2+ levels regulate everything from neurotransmitter release to gene expression to mitochondrial function. With such a central role, internal calcium levels are normally very tightly regulated by redundant layers of compensatory sinks, pumps and sources. But when the aggregated Alzheimer's peptide props open AMPA channels, internal calcium levels go up and stay elevated for a long time. Because of the role of calcium in neurotransmitter release, the neuron cannot respond to incoming stimuli, leading to interruptions in the flow of information within the brain. The interruption translates to cognitive deficits because of the prevalence of AMPA receptors in the hippocampus and cortex—brain regions involved in memory and critical thinking.
In addition to blocking neuronal communication, the calcium dysregulation may also underlie the second major histological finding of Alois Alzheimer: neurofibrillary tangles. These long, bundled fibers are composed of a protein called tau, which has clumped together as a result of extensive chemical modification by protein kinase enzymes. Kinases control many cellular events by adding phosphate groups to proteins, and calcium is a common kinase trigger. Consequently, when calcium levels stay up for long periods of time, kinases are overactivated, and the tau protein becomes a target for phosphate addition. In this state tau is said to be hyperphosphorylated. Hyperphosphorylation not only causes tau to clump together, but it also prevents tau from performing its normal job: stabilizing microtubules that give the cell its structural integrity. The loss of microtubule integrity further damages the neuron, and this damage is proportional to the clinical progression of the disease. The extent of tau modification correlates with the degree of dementia, confirming that brain cells filled with hyperphosphorylated tau (and, by inference, unstable microtubules) are dysfunctional. Between the loss of cytoskeletal support and the calcium flood, the cell loses control of basic metabolic processes and dies (necrosis) or commits suicide (apoptosis).
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