How protein sludge accumulates in Alzheimer's

Researchers have identified a key mechanism by which the protein sludge that kills brain cells accumulates in Alzheimer's disease (AD).

Their findings in mice offer clues to treating AD and also could explain why memory centers of the brain are most affected in the disease.

John Cirrito and colleagues published their findings in the April 10, 2008, issue of the journal Neuron, published by Cell Press.

Central to the pathology of AD is accumulation of toxic protein plaque in the interstitial fluid (ISF) between brain cells. This plaque, which comprises clumps of a small protein called A", interferes with transmission of signals among neurons and ultimately kills them.

A" is produced by the snipping apart of a longer amyloid precursor protein (APP) inside the neuron. However, APP originates at the cell surface, and a key question is how the protein is taken into the cell to be cleaved to produce A".

This question is clinically significant because plaque formation depends on the concentration of A" in ISF, “meaning that elevated levels of ISF A" are likely to hasten the formation of these toxic species,” wrote the researchers.

“Consequently, knowing the factors that regulate ISF A" levels has implications for AD pathogenesis and may provide insights into therapeutic intervention,” they wrote.

In their experiments, the researchers used tiny probes to sample the ISF in mouse brain, in order to measure A" levels. Previous studies in cell cultures had indicated that APP is transported into the neuron through the process called endocytosis. In endocytosis, molecules are enveloped by special structures in the cell membrane and drawn into the cell.

Cirrito and his colleagues showed that endocytosis also transports APP in vivo: When they inhibited endocytosis in the brain cells of the mice, they saw a reduction in A" levels.

In other experiments, the researchers explored why greater activity among neurons in transmitting nerve impulses is connected to an increase in A"—a phenomenon also shown by previous studies. Since nerve impulse transmission depends on endocytosis to transport molecules, the researchers reasoned that this activity-dependent elevation of A" also depends on endocytosis. They found in their experiments that increasing synaptic activity increased ISF A" levels and that this increase depended on endocytosis.

“We estimate that ~70% of ISF A" arises from endocytosis-associated mechanisms, with the vast majority of this pool also dependent on synaptic activity,” concluded the researchers. “These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention,” they wrote.

“Many studies have postulated that the aggregation of A" in both soluble and insoluble forms in the brain is likely a key initiating factor in AD pathogenesis,” they wrote. “Thus, influences on the aggregation process are potentially major treatment targets.”

The researchers also wrote that their finding could help explain why learning and memory are most affected in AD.

“Brain regions that contain the most metabolic activity throughout life, and presumably have the highest levels of neuronal activity, are also the regions most vulnerable to A" accumulation and aggregation in AD patients,” they wrote. “In each of these cases, synaptic activity appears to play a role in regulating A" levels under physiologic conditions. We now identify a cellular pathway, endocytosis, that likely links synaptic activity and A" production.”

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