A Jekyll-and-Hyde enzyme's role in Alzheimer's

December 07, 2005

Researchers have discovered how a brain enzyme important in the development and maintenance of learning and memory also plays a key role in the death of neurons in neurodegenerative disorder such as Alzheimer's disease (AD). They found that the enzyme's transformation from Jekyll to Hyde may be due to abnormal activation of the brain's mechanism to compensate for the damage from such diseases. This compensatory mechanism may also function in normal aging, they said.

In their article in the December 8, 2005, issue of Neuron, Li-Huei Tsai and colleagues said their findings in mice could offer a model to study how normal neural mechanisms can go awry to contribute to the brain degeneration of AD.

The researchers' studies concentrated on a key brain regulatory enzyme called Cdk5. Elevated levels of Cdk5 had been found in the brains of AD patients, as well as elevated levels of a regulatory protein called p25 that is known to hyperactivate Cdk5. Researchers had found that the hyperactivating p25 is produced when the normal regulatory protein for Cdk5, called p35, is snipped into the shorter p25 by another enzyme.

In their experiments, the researchers used mice in which they could switch on p25 at will in the brain's learning and memory center, the hippocampus. In these mice, they found that switching on p25 for only two weeks actually enhanced learning and memory compared to normal mice. The two-week p25 mice could learn more quickly to associate a tone or environment with a mild electrical shock and to find a platform submerged in a pool of murky water.

In contrast, found the researchers, mice in which p25 had been switched on for six weeks showed impaired learning and memory in these tasks. Physiological studies showed that these mice showed significant brain atrophy and loss of hippocampal neurons. The researchers also showed that the two-week pulse of p25 did not cause neurodegeneration and had long-lasting effects on enhancing memory.

Studies of electrophysiological activity in the brains of the mice showed that the two-week p25 animals showed enhancement in the mechanism called "long-term potentiation" (LTP), which is central to learning and memory processes. In contrast, the six-week p25 animals showed a decrease in LTP.

Also, microscopy studies revealed that the two-week p25 animals showed higher connectivity among their neurons than did the six-week p25 animals.

The researchers concluded that their findings "indicate that transient p25 production facilitated learning, whereas the ability to form new memories was impaired by prolonged p25 expression." Also, they wrote that their data suggest that Cdk5 activity plays a role in the adult brain in forming new connections among neurons.

"It is possible that p25 is produced to compensate for the loss of Cdk5 activity during aging," they wrote. "In this scenario, chronic exposure to AD risk factors would further increase p25 levels to a critical concentration that ultimately contributes to neuronal loss.

"Taken together these data suggest that p25 production in vivo is not detrimental per se but can lead to neuronal cell death when p25 levels are chronically high," concluded Tsai and colleagues.

"In summary, it is intriguing that several studies suggest that during the pathogenesis of AD, which manifests over several years, compensatory mechanisms that initially enhance neuroplasticity eventually become maladaptive when chronically activated," they wrote. "A similar scenario can be envisioned for p25. Thus, the present study provides evidence that p25 generation might be a compensatory phenomenon to enhance neuroplasticity. These mice may also serve as a model whereby a factor that promotes plasticity can eventually contribute to neurodegeneration," they wrote.
The researchers include Andre Fischer and Farahnaz Sananbenesi of Harvard Medical School; Petti T. Pang and Bai Lu of the National Institute of Mental Health; and Li-Huei Tsai of Harvard Medical School and Howard Hughes Medical Institute. A.F. is a fellow of the Humboldt society, F.S. is a fellow of the German research foundation (DFG). L.-H.T. is an investigator of the Howard Hughes Medical Institute. This work is partially supported by NIH grant (NS051874) to L.-H.T and by funds from the NIH intramural research program to B.L.

Fischer at al.: "Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory" Publishing in Neuron, Vol. 48, 825-838, December 8, 2005, DOI 10.1016/j.neuron.2005.10.033, www.neuron.org

Cell Press

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.