Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Neuronal Receptor Response May Help Explain Alzheimer’s Memory Loss

13.02.2006


Based on laboratory research, scientists at Georgetown University Medical Center have a new theory as to why people with Alzheimer’s disease have trouble performing even the simplest memory tasks, such as remembering a family member’s name.



That’s because they discovered a physical link between apolipoprotein E (APOE), the transport molecules known to play a role in development of the disease, and glutamate, a brain chemical necessary for establishing human memory.

In a study published in the Journal of Biological Chemistry, the research team specifically found that receptors on the outside of brain nerve cells (neurons) that bind on to APOE and glutamate are connected on the surface of neurons, separated from each other by only a small protein.


While the researchers don’t know why these receptors are linked together, they say inefficient or higher-than-average levels of APOE in the brain could possibly be clogging these binding sites, preventing glutamate from activating the processes necessary to form memories.

“We have found out that two receptors previously thought to have nothing to do with each other do, in fact, interact, leading us to conclude that APOE affects the NMDA glutamate channel that is important in memory,” says the study’s senior author, G. William Rebeck, PhD, associate professor of neuroscience in Georgetown’s Biomedical Graduate Research Organization.

The researchers also hypothesize that this interaction might have something to do with development of Alzheimer’s disease, although they stress that at this early stage of research, this is impossible to prove.

Rebeck and first author Hyang-Sook Hoe, PhD, also of Georgetown, say that laboratory work now underway is attempting to unravel the relationship between APOE and NMDA receptors.

APOE is a protein that helps shuttle cholesterol and other non-soluble lipid particles around the body, moving these substances to where they are needed. All cells have receptors that bind on to APOE so that they can use lipids as needed, such as for quick energy, to store as fat for later use, or to repair wounds.

But researchers now know that APOE does more than distribute lipids, especially in the brain. About a decade ago, scientists linked APOE4, one of the three common forms of APOE, to development of Alzheimer’s disease, although the biological link between the protein and neurodegenerative diseases such as Alzheimer’s is not clear.

Based on recent research, Rebeck and others suspect that, in the brain, APOE also acts as a transporter, picking up lipids and perhaps other material that result from normal brain tissue wear and tear, or from trauma, and moving it to where it can be used or can be cleared away from the brain. Work in Rebeck’s lab found that APOE receptor 2 (ApoEr2), one of the eight different APOE receptor types, is crucial to both the development and operation of a normal brain.

Glutamate is a substance released at the synapse of neurons — the junction between one nerve cell and the next through which chemical messages are transmitted. Glutamate increases the strength of a synaptic response following stimulation. The NMDA glutamate receptor binds on to the drug NMDA, and also on to glutamate, an excitatory neurotransmitter that also stimulates nerve cell activity. Researchers know that the NMDA receptor is needed to produce the long-lasting synaptic response that is necessary in order to establish, or “lay down,” memory, Rebeck says. “The molecular basis of memory depends on NMDA receptor.”

In work leading up to this study, Rebeck and the research team found that adding APOE to neurons in laboratory culture blocked NMDA receptors. In this study, they confirmed through a series of experiments that the receptors for APOE and NMDA interacted, and that the protein that linked the two was PSD95, often found in neural synaptic junctions. Together, they form a multiprotein complex that could presumably be activated by either APOE, NMDA or glutamate.

Rebeck suspects that the APOE4 variant — the one linked to Alzheimer’s disease — is less efficient at removing lipid debris in the brain than is APOE2 or APOE3, and because of this, brain cells secrete more of the faulty protein to do the job. If too much APOE ends up binding to the APOE/NMDA receptor, one of two things could possibly happen, Rebeck says. In one scenario, the receptor becomes over-stimulated due to the accumulating presence of APOE, which could trigger a process called excitotoxicity that results in death of the neruons. Or, in the presence of damage and secreted APOE, the receptor “turns down” its activity — thus, hampering memory formation — until the brain is repaired. “Having damage around tells the brain not to think too much for awhile,” Rebeck says. But if APOE4 cannot clear up accumulating damage, the ability to make new memories, and use old ones, may be increasingly lost.

“This is, of course, speculation, but now we have new avenues in which we can explore the molecular basis of memory and possibly Alzheimer’s disease,” Rebeck says.

The study was funded by the NIH. Co-authors include Ana Pocivavsek and Geetaanjali Chakraborty also of the Department of Neuroscience, Zhanyan Fu, PhD, and Stefano Vicini, PhD, of the Department of Physiology and Biophysics at Georgetown University Medical Center, and Michael D. Ehlers, PhD, of Duke University Medical Center.

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through our partnership with MedStar Health). Our mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis -- or "care of the whole person." The Medical Center includes the School of Medicine and the School of Nursing and Health Studies, both nationally ranked, the world-renowned Lombardi Comprehensive Cancer Center and the Biomedical Graduate Research Organization (BGRO).

Liz McDonald | EurekAlert!
Further information:
http://www.georgetown.edu

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>