Blocking the effects of amyloid b in Alzheimer's disease

During Alzheimer's disease, 'plaques' of amyloid beta (Ab) and tau protein 'tangles' develop in the brain, leading to the death of brain cells and disruption of chemical signaling between neurons. This leads to loss of memory, mood changes, and difficulties with reasoning. New research published in BioMed Central's open access journal Alzheimer's Research & Therapy, has found that up-regulating the gene Hes1 largely counteracted the effects of Ab on neurons, including preventing cell death, and on GABAergic signaling.

31 july 2012--The exact mechanism behind how Ab contributes to Alzheimer's disease is not yet fully understood, however researchers from Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER) in Spain recently discovered that Ab interferes with the normal activity of nerve growth factor (NGF). One of the actions of NGF is activating the protein Hes1, a transcription factor required to turn on other genes. Without this factor GABAergic signaling within the brain decreases.

Using gene therapy techniques, Pedro Chacón and Alfredo Rodríguez-Tébar augmented the amount of Hes1 in cultured neurons. Increasing the amount of Hes1, directly or by activating the protein NF-kB (which in turn up-regulate the cell's own Hes1), abolished the effect of Ab and prevented neuron death. Additionally another growth factor, TGFb, which can also activate NF-kB, was able to prevent the effects of Ab on neurons by improving levels of Hes1.

Pedro Chacón explained, "Ab usually decreases the length of dendrites and GABAergic connectivity of neurons, however these effects were completely reversed by Hes1, NF-kB, and TGFb. When we grew neurons in a concentration of Ab which normally kills most cells, 50% of the neurons with extra Hes1 were able to survive."

These results demonstrate that neurons can be protected from the effects of Ab by increasing the amount of Hes1 in the cells. By clarifying the roles of NGF or TGFb in Hes1 protection this research provides strategies for limiting the effects of Alzheimer's disease.

More information: Increased expression of the homologue of Enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector Pedro J Chacon and Alfredo Rodriguez-Tebar Alzheimer's Research & Therapy (in press)

Provided by BioMed Central

Novel role of protein in generating amyloid-beta peptide

30 april 2009--A defining hallmark of Alzheimer's disease is the accumulation of the amyloid β protein (Aβ), otherwise known as "senile plaques," in the brain's cortex and hippocampus, where memory consolidation occurs. Researchers at the University of California, San Diego School of Medicine have identified a novel protein which, when over-expressed, leads to a dramatic increase in the generation of Aβ. Their findings, which indicate a potential new target to block the accumulation of amyloid plaque in the brain, will be published in the May 1 issue of the Journal of Biological Chemistry.

"The role of the multi-domain protein, RANBP9, suggests a possible new therapeutic target for Alzheimer's disease," said David E. Kang, PhD, assistant professor of neurosciences at UC San Diego and director of this study.

The neurotoxic protein Aβ is derived when the amyloid precursor protein (APP) is "cut" by two enzymes, β-secretase (or BACE) and γ-secretase (or Presenilin complex.) However, inhibiting these enzymes in order to stop the amyloid cascade has many negative side effects, as these enzymes also have various beneficial uses in brain cells. So the researchers looked for an alternative way to block the production of amyloid beta.

In order for cleavage to occur, the APP needs to travel to cholesterol-enriched sites within the cell membrane called RAFTS, where APP interacts with the two enzymes. It is this contact that the researchers sought to block.

Kang explains that the researchers identified the RANBP9 protein by studying low density lipoprotein receptor-related protein (LRP), a protein that rapidly shuttles Aβ out of the brain and across the blood-brain barrier to the body, where it breaks down into harmless waste products. A small segment of LRP can also stimulate Aβ generation, and the scientists narrowed this segment down to a 37-amino-acid stretch that can lead to changes in Aβ.

"RANBP9 is one of the proteins we identified that interacted with this LRP segment, but one that had never before been associated with disease-related neuronal changes," said Kang. "We discovered that this protein interacts with three components involved in Aβ generation – LRP, APP and BACE1 – and appears to 'scaffold' them into a structure."

Kang explained that these three components must come together to result in the first cut or cleaving that leads to production of Aβ. To test this, the scientists knocked out RANBP9 in the cell, and discovered that 60% less Aβ was produced.

"This unique factor enhances the production of beta amyloid," said Kang. "Inhibiting the RANBP9 protein may offer an alternative approach to therapy, by preventing contact between APP and the enzyme that makes the cut essential to produce amyloid plaques." The researchers' next step is to verify these findings in animal models.

According to the Alzheimer's Association, an estimated 5.3 million people have Alzheimer's disease in the United States alone, and a new case is diagnosed every seven seconds.

Madepalli K. Lakshmana, Ph.D., the study's first author, added that "this study is the first to identify RANBP9 as a target to potentially inhibit the movement of APP to RAFTS so that amyloid beta peptide generation can be prevented. As such, a small molecule drug that can reduce the RANBP9 protein levels could offer an effective treatment for Alzheimer's disease."

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Additional contributors to the study include Il-Sang Yoon, Eunice Chen and Edward H. Koo, of UC San Diego Department of Neurosciences; and Elizabetta Bianchi from the Institut Pasteur in Paris.

This work was supported in part by the American Health Assistance Foundation, the Alzheimer's Association, and the National Institutes of Health, National Institute on Aging.

Amyloid-Beta Changes Seen in Injured Brains

By Michael Smith
ST. LOUIS, 29 aug 2008-- In patients with brain injury, recovery is correlated with increased levels of some of the peptides associated with Alzheimer's disease, researchers here said. The finding emerged from the first direct measurement of amyloid-beta levels in the interstitial fluid of the brains of living humans, according to David Brody, M.D., Ph.D., of Washington University and colleagues. The analysis, using a technique called microdialysis, showed that levels of amyloid-beta rose as patients' neurological status improved and fell when it worsened, Dr. Brody and colleagues reported in the Aug. 29 issue of Science. He and colleagues undertook the study -- in 18 patients already undergoing invasive intracranial monitoring after either brain trauma or aneurysmal subarachnoid hemorrhage -- to increase their understanding of the dynamics of amyloid-beta peptides.
Amyloid-beta (especially the 42-amino acid form) plays a central role in the development of Alzheimer's, and people with brain injuries are known to be at higher risk of later developing the illness.
"Amyloid-beta is normally present in the cerebrospinal fluid and it was generally believed to be a normal component of the brain extracellular fluid," he said. "This is the first time that has been demonstrated."
The key finding of the analysis was the close link between neurological status, as measured by the Glasgow Coma Score, and levels of amyloid-beta, he said.
Because the clinical significance of a one-point change in the coma score isn't clear, the researchers assessed changes in the amyloid-beta levels only when the score changed by two or more points.

The correlation "was markedly strong," they found, with a Spearman r of 0.82, which was significant at P<0.0001, and remained "quite robust" when the analysis allowed one-point coma score changes. (The Spearman r was 0.52, which was also significant at P<0.0001).
The correlation was present both in patients with traumatic injury and subarachnoid hemorrhage, Dr. Brody and colleagues reported.
Levels of amyloid-beta were also correlated with physiological markers, they said. Specifically, they were:
Positively correlated with glucose in the brain interstitial fluid (where the Spearman r was 0.45, significant at P<0.0001).
Negatively correlated with the lactate/pyruvate ratio, with a Spearman r of minus 0.40, which was significant at P<0.0001.
Negatively correlated with elevated intracranial pressure (greater than 20 mm Hg) with a Spearman r of minus 0.56, which was significant at P<0.0001.
Negatively correlated with extremes of cerebral temperature, with a Spearman r of minus 0.26, which was significant at P<0.0001.
One implication of the finding is that the level of amyloid-beta reflects brain activity.
The "most likely" explanation, Dr. Brody said, is that the levels rose as patients improved "because synaptic activity in their brains increased concomitantly with the improvement in neurological status."
The study is only a first step in understanding how amyloid-beta levels vary over time, Dr. Brody said. Among other things, the researchers were unable to measure what was happening within the cells of the damaged brains, so that analysis is incomplete.
One immediate clinical implication, he said, is that amyloid-beta levels "could be used as a marker for neurological status," which is now difficult for clinicians to measure.
The study was supported by the NIH, a Burroughs Wellcome Career Award in the Biomedical Sciences, and the Cure Alzheimer's Fund. Eli Lilly and Co. provided antibodies. The researchers reported no conflicts.
Primary source: ScienceSource reference:Brody DL, et al "Amyloid-b dynamics correlate with neurological status in the injured human brain" Science 2008; 321: 1221-24.