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Alzheimer's-associated Enzyme Can Disrupt Neural Activity In The Brain

Date:
June 18, 2007
Source:
Massachusetts General Hospital
Summary:
An enzyme involved in the formation of the amyloid-beta protein associated with Alzheimer's disease can also alter the mechanism by which signals are transmitted between brain cells, the disruption of which can cause seizures. These findings may explain the increased incidence of seizures in Alzheimer's patients, and suggest that potential treatments that block this enzyme may alleviate their occurrence

An enzyme involved in the formation of the amyloid-beta protein associated with Alzheimer's disease can also alter the mechanism by which signals are transmitted between brain cells, the disruption of which can cause seizures. These findings from researchers at the MassGeneral Institute for Neurodegenerative Disorders (MGH-MIND) may explain the increased incidence of seizures in Alzheimer's patients and suggest that potential treatments that block this enzyme -- called beta-secretase or BACE -- may alleviate their occurrence.

"We have found a molecular pathway by which BACE can modulate the activity of sodium channels on neuronal cell membranes," says study leader Dora Kovacs, PhD, director of the Neurobiology of Disease Laboratory in the Genetics and Aging Research Unit at MGH-MIND. "That implies that elevated BACE activity may be responsible for the seizures frequently observed in Alzheimer's patients."

Alzheimer's disease is characterized by plaques within the brain of the toxic amyloid-beta protein. Amyloid-beta is formed when the larger amyloid precursor protein (APP) is clipped by two enzymes -- BACE and gamma-secretase -- which releases the amyloid-beta fragment.

Signaling impulses in nerve cells are transmitted via voltage-gated sodium channels, structures on the cell membrane that transmit electrochemical signal by admitting charged sodium particles into the cell's interior. Sodium channels consist of an alpha subunit, which makes up the body of the channel, and one or two beta subunits that help to regulate the channels' activity.

Previous studies from Kovacs' team and others showed that the BACE and gamma-secretase enzymes that release amyloid-beta from APP also act on the beta2 subunit of neuronal sodium channels. The current study was designed to examine how this processing of the beta2 subunit may alter neuronal function.

Lead author Doo Yeon Kim, PhD, and colleagues first confirmed 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. A series of experiments using brain tissue from animal models and from Alzheimer's patients revealed the following series of cellular events: Elevated levels of the free beta2 segment within the cell appear to increase production of the alpha subunits, but those molecules are not incorporated into new sodium channels on the cell surface. The resulting deficit of membrane sodium channels inhibits the passage of neuronal signals into and through the cells.

Neuronal sodium-channel dysfunction is known to cause seizures in both mice and humans. In a supplement to the current paper the investigators present evidence that sodium channel metabolism is altered in the brains of Alzheimer's patients 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 explains. "However, complete inhibition of BACE activity could interfere with the enzyme's normal regulation of sodium channels, so therapeutic strategies using those inhibitors will need to be carefully designed." Kovacs is an associate professor of Neurology at Harvard Medical School.

The report will appear in the journal Nature Cell Biology and is receiving early online release.


Story Source:

The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.


Cite This Page:

Massachusetts General Hospital. "Alzheimer's-associated Enzyme Can Disrupt Neural Activity In The Brain." ScienceDaily. ScienceDaily, 18 June 2007. <www.sciencedaily.com/releases/2007/06/070617164039.htm>.
Massachusetts General Hospital. (2007, June 18). Alzheimer's-associated Enzyme Can Disrupt Neural Activity In The Brain. ScienceDaily. Retrieved September 15, 2014 from www.sciencedaily.com/releases/2007/06/070617164039.htm
Massachusetts General Hospital. "Alzheimer's-associated Enzyme Can Disrupt Neural Activity In The Brain." ScienceDaily. www.sciencedaily.com/releases/2007/06/070617164039.htm (accessed September 15, 2014).

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