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Alzheimer's-associated Enzyme Linked to Seizures

Boffins have found that an enzyme beta-secretase or BACE, involved in the formation of the amyloid-beta protein linked with Alzheimer's disease can also alter neural activity in the brain , whose disruption might lead to seizures.

The study might put light on the high occurrence of seizures in Alzheimer's patients and suggests that treatments that might block this enzyme could lessen the incidences of seizures. Alzheimer's disease is marked by toxic amyloid-beta protein plaques in the brain which are formed when the larger amyloid precursor protein (APP) is clipped by two enzymes, BACE and gamma-secretase, which release the amyloid-beta fragment.

The study was conducted by a team of researchers led by Dora Kovacs at the MassGeneral Institute for Neurodegenerative Disorders (MGH-MIND). Earliers studies have shown that the BACE and gamma-secretase enzymes also work on the beta2 subunit of neuronal sodium channels.

Sodium channels comprise an alpha subunit, which forms the channel's body, and one or two beta subunits that checks the activity of the channel. Voltage-gated sodium channels transmit signalling impulses in nerve cells. As part of the study, to test how the processing of the beta2 subunit modify neuronal function, researchers conducted tests using brain tissue from animal models and from Alzheimer's patients after making sure that the beta2 subunit, similar to APP, can be acted on by BACE and gamma-secretase, releasing a portion of the beta2 molecule from the cell membrane.

The study found that increased levels of the free beta2 segment in the cell might increase the formation of the alpha subunits, but those molecules were not integrated into new sodium channels on the cell surface. The resulting scarcity of membrane sodium channels inhibited the path of neuronal signals into and through the cells.

"We have found a molecular pathway by which BACE can modulate the activity of sodium channe ls on neuronal cell membranes," Nature Cell Biology quoted Kovacs, as saying. Researchers suggested that sodium channel metabolism, whose dysfunction is known to cause seizures in both mice and humans is altered in the brains of Alzheimer's patients as compared with non-demented individuals of similar age.

"Our study suggests that the BACE inhibitors currently being developed to reduce amyloid-beta generation in Alzheimer's disease patients may also help prevent seizures by alleviating disrupted neural activity," Kovacs said.


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