Featured Research

from universities, journals, and other organizations

Key Function Of Nervous System Enzyme Found; Impact On Drug Development Against Alzheimer's

Date:
September 29, 2006
Source:
Max Delbrück Center For Molecular Medicine
Summary:
Ever since scientists first elucidated the molecular mechanisms underlying the pathology and loss of nerve cells in Alzheimer's disease, drug companies have been working to develop drugs which will inhibit the outbreak of this severe form of dementia. Now researchers in Munich and Berlin (Germany) have discovered that an enyzme which has a central causal role in Alzheimer's disease happens also to have a key function in the normal development of the nervous system. This enzyme, beta-secretase or BACE1, ensures that nerve fibers (axons) are adequately isolated with sheaths of myelin, enabling rapid conduction of electrical impulses, as well as preventing short-circuits, akin to plastic insulation on electrical wires.

Section through nerve fibres within the sciatic nerve as seen under the electron microscope: the axons (nerve cell projections, pink) are only poorly surrounded by a myelin sheath (generated by Schwann cells, coloured blue) following inactivation of the gene encoding BACE1, which controls the myelination process (right panel). The nerve fibres in a control animal (left panel, BACE1 gene is intact) are in contrast surrounded by thick myelin sheaths (dark rings).
Credit: Dr. Alistair Garratt / Copyright: MDC

Ever since scientists first elucidated the molecular mechanisms underlying the pathology and loss of nerve cells in Alzheimer's disease, drug companies have been working to develop drugs which will inhibit the outbreak of this severe form of dementia. Now researchers in Munich and Berlin (Germany) have discovered that an enyzme which has a central causal role in Alzheimer's disease happens also to have a key function in the normal development of the nervous system. This enzyme, beta-secretase or BACE1, ensures that nerve fibers (axons) are adequately isolated with sheaths of myelin, enabling rapid conduction of electrical impulses, as well as preventing short-circuits, akin to plastic insulation on electrical wires.

Related Articles


The discovery of the new key function of BACE1 by Dr. Michael Willem (Ludwig-Maximilians-Universität München, LMU), Dr. Alistair Garratt, Professor Carmen Birchmeier (both at the Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch), Professor Christian Haass (LMU) will have an impact on the development of Alzheimer's drugs. Using genetically modified mice, researchers had been previously able to show that Alzheimer's comes to a halt when the gene encoding BACE1 is inactivated. However, the researchers in Germany have now discovered that these mutant mice lack fully developed myelin sheaths, a defect which can result in nerve damage (neuropathies). Professor Christian Haass points out: "These findings allow us for the first time to also look very closely at the side effects of Alzheimer`s inhibitors." Their findings in cooperation with scientists from the US and Belgium have now been published in Science Express, the online issue of the journal Science.

Alzheimer`s disease is an illness associated with aging, and characterized by the widespread death of nerve cells within the brain. One of the principal pathological hallmarks of the disease is the presence of insoluble aggregates of a specific protein fragment, called beta-amyloid. Amyloid peptides are generated through the action of protein-cutting enzymes (proteases), including BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1), which cleave the amyloid precursor protein (APP) into pieces, and thereby release beta-amyloid from the surface of nerve cells. When the gene encoding BACE1 is inactivated or when BACE1 action is inhibited pharmacologically, the production of harmful amyloid from APP is prevented and Alzheimer's disease fails to develop.

However, the researchers in Germany have now discovered that the insulating myelin sheaths of peripheral nerves fail to develop properly after inactivation of the gene encoding BACE1. In addition, the bundling of fibers of small diameter pain-sensing nerve cells into so-called Remak-bundles is abnormal. Intriguingly, the researchers found high levels of an uncleaved form of a protein, type III Neuregulin-1, in the nerve cells of BACE1 mutant mice.

Dr. Alistair Garratt and Professor Carmen Birchmeier were the first to demonstrate some years ago that nerve cells produce type III Neuregulin-1 to attract Schwann cells, the insulating glia of the peripheral nervous system, to the nerve fibers. These Schwann cells migrate along the nerve fibers and produce the myelin sheaths.

The findings of the researchers at the MDC, showing that BACE1 regulates the development of the myelin sheath, together with the discovery by Dr. Willem and Prof. Haass in Munich that BACE1 specifically cleaves Neuregulin-1, shed light on the newly characterized physiological function of BACE1: it is required to process Neuregulin-1 into a form that stimulates the Schwann cells to build up thick layers of myelin. This contrasts with the function of BACE1 in Alzheimer`s disease, where its activity in cutting the protein APP is detrimental to the nervous system.

After birth, mice produce much BACE1 to trigger the insulation of nerve fibers with myelin. "BACE1 has therefore also positive functions, not only bad ones", explained Dr. Garratt. If the myelin sheath is missing, or inadequately formed, it can eventually lead to nerve dysfunction, as the researchers found in mice lacking a functional BACE1 gene. "We have thus been able to bring together the field of developmental biology with that focusing on neurodegenerative diseases," commented Dr. Garratt.

The researchers would predict that inhibition of BACE1 in the adult animal should not impact on the myelination of peripheral nerves, as Neuregulin-dependent signals are then no longer required for the maintenance of myelin sheaths. The elucidation of a physiological function of BACE1 should however allow the development of inhibitors which prevent specifically the generation of amyloid in the brain.


Story Source:

The above story is based on materials provided by Max Delbrück Center For Molecular Medicine. Note: Materials may be edited for content and length.


Cite This Page:

Max Delbrück Center For Molecular Medicine. "Key Function Of Nervous System Enzyme Found; Impact On Drug Development Against Alzheimer's." ScienceDaily. ScienceDaily, 29 September 2006. <www.sciencedaily.com/releases/2006/09/060925064105.htm>.
Max Delbrück Center For Molecular Medicine. (2006, September 29). Key Function Of Nervous System Enzyme Found; Impact On Drug Development Against Alzheimer's. ScienceDaily. Retrieved November 23, 2014 from www.sciencedaily.com/releases/2006/09/060925064105.htm
Max Delbrück Center For Molecular Medicine. "Key Function Of Nervous System Enzyme Found; Impact On Drug Development Against Alzheimer's." ScienceDaily. www.sciencedaily.com/releases/2006/09/060925064105.htm (accessed November 23, 2014).

Share This


More From ScienceDaily



More Mind & Brain News

Sunday, November 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Could Your Genes Be The Reason You're Single?

Could Your Genes Be The Reason You're Single?

Newsy (Nov. 21, 2014) — Researchers in Beijing discovered a gene called 5-HTA1, and carriers are reportedly 20 percent more likely to be single. Video provided by Newsy
Powered by NewsLook.com
Milestone Birthdays Can Bring Existential Crisis, Study Says

Milestone Birthdays Can Bring Existential Crisis, Study Says

Newsy (Nov. 21, 2014) — Researchers find that as people approach new decades in their lives they make bigger life decisions. Video provided by Newsy
Powered by NewsLook.com
You Don't Have To Be Alcohol Dependent To Need Treatment

You Don't Have To Be Alcohol Dependent To Need Treatment

Newsy (Nov. 21, 2014) — A study by the Centers for Disease Control and Prevention found 9 out of 10 excessive drinkers in the country are not alcohol dependent. Video provided by Newsy
Powered by NewsLook.com
Your Complicated Job Might Keep Your Brain Young

Your Complicated Job Might Keep Your Brain Young

Newsy (Nov. 20, 2014) — Researchers at the University of Edinburgh found the more complex your job is, the sharper your cognitive skills will likely be as you age. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins