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Wednesday, June 29

"Age-Related Memory Loss" Has Nothing to Do with Alzheimer's

VIDEO & ARTICLE - DIAGNOSING MEMORY LOSS:

Forgetful? That does not mean Alzheimer's. Nobel-prize winner Dr. Eric Kandel discovered a key reason we become forgetful. He calls it "Age-Related Memory Loss". It's got nothing to do with dementia. It happens even when we're perfectly healthy. Find out why it occurs.



A team of Columbia University Medical Center (CUMC) researchers, led by Nobel laureate Eric R. Kandel, MD, has found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible. The study, conducted in postmortem human brain cells and in mice, also offers the strongest causal evidence that age-related memory loss and Alzheimer’s disease are distinct conditions. The findings were published in the online edition of Science Translational Medicine.

Health Consequences

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The researchers have identified a protein—RbAp48—that, when increased in aged wild-type mice, improves memory back to that of young wild-type mice. In the image, yellow shows the increased RbAp48 in the dentate gyrus. Image credit: Elias Pavlopoulos, PhD/Columbia University Medical Center

The researchers have identified a protein—RbAp48—that, when increased in aged wild-type mice, improves memory back to that of young wild-type mice. In the image, yellow shows the increased RbAp48 in the dentate gyrus. Image credit: Elias Pavlopoulos, PhD/Columbia University Medical Center
“Our study provides compelling evidence that age-related memory loss is a syndrome in its own right, apart from Alzheimer’s. In addition to the implications for the study, diagnosis, and treatment of memory disorders, these results have public health consequences,” said Dr. Kandel, who is University Professor & Kavli Professor of Brain Science, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, director of the Kavli Institute for Brain Science, and senior investigator, Howard Hughes Medical Institute, at CUMC. Dr. Kandel received a share of the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.

The hippocampus, a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Studies have shown that Alzheimer’s disease hampers memory by first acting on the entorhinal cortex (EC), a brain region that provides the major input pathways to the hippocampus. It was initially thought that age-related memory loss is an early manifestation of Alzheimer’s, but mounting evidence suggests that it is a distinct process that affects the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the EC.

“Until now, however, no one has been able to identify specific molecular defects involved in age-related memory loss in humans,” said co-senior author Scott A. Small, MD, the Boris and Rose Katz Professor of Neurology and director of the Alzheimer’s Research Center at CUMC.

Direct Evidence

The current study was designed to look for more direct evidence that age-related memory loss differs from Alzheimer’s disease. The researchers began by performing microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their EC, which served as controls since that brain structure is unaffected by aging. The analyses identified 17 candidate genes that might be related to aging in the DG. The most significant changes occurred in a gene called RbAp48, whose expression declined steadily with aging across the study subjects.

To determine whether RbAp48 plays an active role in age-related memory loss, the researchers turned to mouse studies. “The first question was whether RbAp48 is downregulated in aged mice,” said lead author Elias Pavlopoulos, PhD, associate research scientist in neuroscience at CUMC. “And indeed, that turned out to be the case—there was a reduction of RbAp48 protein in the DG.”

Normal Memory

When the researchers genetically inhibited RbAp48 in the brains of healthy young mice, they found the same memory loss as in aged mice, as measured by novel object recognition and water maze memory tests. When RbAp48 inhibition was turned off, the mice’s memory returned to normal.

The researchers also did functional MRI (fMRI) studies of the mice with inhibited RbAp48 and found a selective effect in the DG, similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 inhibition on the DG was accompanied by defects in molecular mechanisms similar to those found in aged mice. The fMRI profile and mechanistic defects of the mice with inhibited RbAp48 returned to normal when the inhibition was turned off.

"We Were Astonished"

In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice. “We were astonished that not only did this improve the mice’s performance on the memory tests, but their performance was comparable to that of young mice,” said Dr. Pavlopoulos.

“The fact that we were able to reverse age-related memory loss in mice is very encouraging,” said Dr. Kandel. “Of course, it’s possible that other changes in the DG contribute to this form of memory loss. But at the very least, it shows that this protein is a major factor, and it speaks to the fact that age-related memory loss is due to a functional change in neurons of some sort. Unlike with Alzheimer’s, there is no significant loss of neurons.”

Finally, the study data suggest that RbAp48 protein mediates its effects, at least in part, through the PKA-CREB1-CBP pathway, which the team had found in earlier studies to be important for age-related memory loss in the mouse. According to the researchers, RbAp48 and the PKA-CREB1-CBP pathway are valid targets for therapeutic intervention. Agents that enhance this pathway have already been shown to improve age-related hippocampal dysfunction in rodents.

The Right Target

“Whether these compounds will work in humans is not known,” said Dr. Small. “But the broader point is that to develop effective interventions, you first have to find the right target. Now we have a good target, and with the mouse we’ve developed, we have a way to screen therapies that might be effective, be they pharmaceuticals, nutraceuticals, or physical and cognitive exercises.”

“There’s been a lot of hand-wringing over the failures of drug trials based on findings from mouse models of Alzheimer’s,” Dr. Small said. “But this is different. Alzheimer’s does not occur naturally in the mouse. Here, we’ve caused age-related memory loss in the mouse, and we’ve shown it to be relevant to human aging.”

The paper is titled, “A Molecular Mechanism for Age-Related Memory Loss: The Histone Binding Protein RbAp48.” The other contributors are Sidonie Jones, Stylianos Kosmidis, Maggie Close, Carla Kim, and Olga Kovalerchik, all at CUMC.

The authors declare no financial or other conflicts of interests.

The study was supported by grants from the Howard Hughes Medical Institute, the James S. McDonnell Foundation, the Broitman Foundation, the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., the McKnight Brain Research Foundation, and the National Institute on Aging (AG034618).
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The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer’s, Parkinson’s, and other age-related brain diseases and to discover ways to prevent and cure these diseases. It has partnered with the Gertrude H. Sergievsky Center at Columbia University Medical Center, which was established by an endowment in 1977 to focus on diseases of the nervous system, and with the Departments of Pathology & Cell Biology and of Neurology to allow the seamless integration of genetic analysis, molecular and cellular studies, and clinical investigation to explore all phases of diseases of the nervous system. For more information, visit The Taub Institute at http://www.cumc.columbia.edu/dept/taub/.

The Department of Neuroscience at Columbia University Medical Center

CUMC’s Department of Neuroscience, whose faculty includes two Nobel laureates, focuses on fundamental aspects of neural circuit development, organization, and function, using cutting-edge biophysical, cellular imaging, and molecular genetic approaches. Its faculty have backgrounds in a range of fields, including molecular and cell biology, systems neuroscience, theoretical neuroscience, and biophysics.

The department has 23 faculty members with primary appointments and an additional 12 faculty members with secondary appointments, as well as 40 postdoctoral researchers. The department also administers the university-wide doctoral program in neurobiology and behavior, which has approximately 90 graduate students. Interdisciplinary research is facilitated by widespread collaboration among labs, as well as with other Columbia centers and institutes, including the Mahoney-Keck Center for Brain & Behavior, the Kavli Institute for Brain Science, the Center for Theoretical Neuroscience, the Center for Motor Neuron Biology and Disease, the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, and the Sackler Institute for Developmental Psychobiology. The department also has strong ties to the Faculty of Arts and Sciences on the university’s Morningside Campus.

The Mortimer B. Zuckerman Mind Brain Behavior Institute

Columbia University’s Mortimer B. Zuckerman Mind Brain Behavior Institute is an interdisciplinary center for scholars across the university, created on a scope and scale to explore the human brain and behavior at levels of inquiry from cells to society. The institute’s leadership, which includes two Nobel Prize-winning neuroscientists, and many of its principal investigators will be based at the 450,000-square-foot Jerome L. Greene Science Center, now rising on the university’s new Manhattanville campus. In combining Columbia’s preeminence in neuroscience with its strengths in the biological and physical sciences, social sciences, arts, and humanities, the institute provides a common intellectual forum for research communities from Columbia University Medical Center, the Faculty of Arts and Sciences, the School of Engineering and Applied Science, and professional schools on both the Morningside Heights and Washington Heights campuses. Their collective mission is to further our understanding of the human condition and to find cures for disease.

SOURCE:
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

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  1. This comment has been removed by the author.

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  2. As we can read in the text above, professor Scott A. Small (the co-senior author of the article above) , he talked about “ to screen therapies that might be effective” as the use of Nutraceutical Supplements to protects the dentatus gyrus and the entorrhinal cortex.


    There are some scientific research articles in PubMed , that shows that the Nutraceutical Supplement L-CARNOSINE can gives neuroprotection to that brain structures , as just the Dentatus Gyrus . (As in the part of the article that I pasted bellow).

    My suggestion is that researchers and pharma companies could uses the food supplements ( nutraceutical supplements) as Glucuronolactone, Acetyl L Carnitine and L-Carnosine , as pharmacological bases to develops others supplements or medicine drugs , with the same mechanisms of actions of the nutraceutical supplements above (as L-carnosine,etc) , but with much more effectiviness and powerful effects.

    I pasted bellow some parts of scientific articles about fhe neuroprotection effects of L-CARNOSINE :

    1) Title of the article published in 2009 : “. Effects of Carnosine on Long-Term Plasticity of Medial Perforant Pathway/Dentate Gyrus Synapses in : an in vivo model ” ( author : Süer, Cem) –published in the american neuroscience journal called Experimental Brain Research , where we can read that :

    “ ... The objective of this study was to examine the effect of carnosine on the hippocampal-dependent learning in perforant pathway/DENTATE GYRUS synapses...” and that “ ... . The present experiment provides the first evidence that CARNOSINE may play a role in synaptic plasticity in DENTATE GYRUS in vivo...”


    2) Title of the article published in 2004 : “ Is Carnosine a Naturally Occurring Suppressor of Oxidative Damage in Olfactory Neurones ? “ (Author- Hipkiss AR., from the London School of Medicine), published in the american sicence journal called:Journal Rejuvenation Research Experimental Therapeutics,where we can read :

    “...neurons from olfactory lobes of Alzheimer's patients exhibit oxidative stress and it is well known that olfactory dysfunction frequently accompanies neurodegeneration. The Olfactory Lobe is normally enriched in Carnosine, a relatively non-toxic dipeptide which possesses functions (anti-oxidant, antiglycator, scavenger of zinc and copper íons ) that are likely to suppress oxidative
    stress. It is suggested that carnosine's therapeutic potential should be
    explored in Olfactory Tissue...”


    3) Title of the article published in 1997 : “ Carnosine-Induced Inward Currents In Rat Olfactory Bulb Neurons in Cultured Slices.” (author : Authors Kanaki K. , from the Hokkaido University, Japan., where we can read that :

    “ ... Olfactory neurons are rich in carnosine, which is regarded as a possible neurotransmitter between olfactory neurons and the olfactory bulb neurons...” ‘... The present results suggest that carnosine
    serves as an excitable neuroeffector between olfactory neurons and olfactory bulb neurons...”


    In a scientific article of the Department of Physical Education, International Pacific University, Japan , published in the scientific Journal of the International Society of Sport Nutrition with the title: "

    Expression profiles of CARNOSINE synthesis–related genes in mice after ingestion of CARNOSINE or ß-alanine " ,
    we can see that a natural source of CARNOSINE is the chicken breast .I pasted bellow some sentences of the article :

    "... So, the majority of the previous research relating to the ergogenic effects of elevated muscle carnosine content via chicken breast extract..." and that :
    "... Recently, carnosine synthase was purified from chicken pectoral muscle and identified as an ATP-grasp domain-containing protein 1 (ATPGD1) ..."

    But the pure Carnosine powder it is easier to takes and more effective than the content of carnosine in the chicken breast. But to eat chicken breast it is interesting as a "nutraceutical food" to strengh and for neuroprotection.

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  3. This comment has been removed by a blog administrator.

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  4. This comment has been removed by the author.

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  5. Although it has been proved not have necessary relations with Alzheimer's, it's indeed easy to be related to this common disease.

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  6. A healthy lifestyle may prevent age-related memory loss:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1123445/

    ReplyDelete
  7. Healthy bones are also important for avoiding age-related memory loss:

    https://bigthink.com/videos/eric-kandel-on-memory-loss-lifelong-learning-and-brain-health

    ReplyDelete

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