Caffeine Boosts Dementia-Fighting Enzyme

I bet your incompetent stroke hospital will not create a 24 hour a day coffee station. And if you are not catheterized this is great therapy for walking to the bathroom in time. There are NO excuses for such incompetence.

 Caffeine Boosts Dementia-Fighting Enzyme

 DIET VIDEO + ARTICLE:

Caffeine increases the enzyme called NMNAT2 in the brain. This creates a chemical 'blockade' against dementia. Learn how caffeine and 23 other compounds can protect you.

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BLOOMINGTON, Ind. -- A study by Indiana University researchers has identified 24 compounds -- including caffeine -- with the potential to boost an enzyme in the brain shown to protect against dementia.

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The protective effect of the enzyme, called NMNAT2, was discovered last year through research conducted at IU Bloomington. The new study appears today in the journal Scientific Reports.

"This work could help advance efforts to develop drugs that increase levels of this enzyme in the brain, creating a chemical 'blockade' against the debilitating effects of neurodegenerative disorders," said Hui-Chen Lu, who led the study. Lu is a Gill Professor in the Linda and Jack Gill Center for Biomolecular Science and the Department of Psychological and Brain Sciences, a part of the IU Bloomington College of Arts and Sciences.

Two Roles in the Brain

Previously, Lu and colleagues found that NMNAT2 plays two roles in the brain: a protective function to guard neurons from stress and a “chaperone function” to combat misfolded proteins called tau, which accumulate in the brain as "plaques" due to aging. The study was the first to reveal the "chaperone function" in the enzyme.

Misfolded proteins have been linked to neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, as well as amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease. Alzheimer’s disease, the most common form of these disorders, affects over 5.4 million Americans, with numbers expected to rise as the population ages.

To identify substances with the potential to affect the production of the NMNAT2 enzyme in the brain, Lu’s team screened over 1,280 compounds, including existing drugs, using a method developed in her lab. A total of 24 compounds were identified as having potential to increase the production of NMNAT2 in the brain.

Caffeine Improves

One of the substances shown to increase production of the enzyme was caffeine, which also has been shown to improve memory function in mice genetically modified to produce high levels of misfolded tau proteins.

Lu's earlier research found that mice altered to produce misfolded tau also produced lower levels of NMNAT2.

To confirm the effect of caffeine, IU researchers administered caffeine to mice modified to produce lower levels of NMNAT2. As a result, the mice began to produce the same levels of the enzyme as normal mice.

Rolipram

Another compound found to strongly boost NMNAT2 production in the brain was rolipram, an "orphaned drug" whose development as an antidepressant was discontinued in the mid-1990s. The compound remains of interest to brain researchers due to several other studies also showing evidence it could reduce the impact of tangled proteins in the brain.

Other compounds shown by the study to increase the production of NMNAT2 in the brain -- although not as strongly as caffeine or rolipram -- were ziprasidone, cantharidin, wortmannin and retinoic acid. The effect of retinoic acid could be significant since the compound derives from vitamin A, Lu said.

An additional 13 compounds were identified as having potential to lower the production of NMNAT2. Lu said these compounds are also important because understanding their role in the body could lead to new insights into how they may contribute to dementia.

"Increasing our knowledge about the pathways in the brain that appear to naturally cause the decline of this necessary protein is equally as important as identifying compounds that could play a role in future treatment of these debilitating mental disorders," she said.

MORE INFORMATION:

• Other researchers on the study were assistant research scientist Yousuf O. Ali and graduate student Gillian Bradley, both of the Linda and Jack Gill Center for Biomolecular Science at IU Bloomington. Ali and Lu are co-corresponding authors on the paper.
• This study was funded by the National Institutes of Health's National Institute of Neurological Disorders and Stroke and the Belfer Family Foundation.

SOURCE:

• Indiana University Bloomington

Rolipram improves cognition, reduces anxiety- and despair-like behaviors and impacts hippocampal neuroplasticity after transient global cerebral ischemia

Is your doctor doing anything for you despair, anxiety or cognition. Mine did nothing.  I do wonder how they know mice are despairing or have anxiety?
http://www.sciencedirect.com/science/article/pii/S0306452216300495

• Lígia Mendes Soares^a,
• Jochen De Vry^b,
• Harry W.M. Steinbusch^b,
• Humberto Milani^a,
• Jos Prickaerts^b,
• Rúbia M. Weffort de Oliveira^{a, ,}

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doi:10.1016/j.neuroscience.2016.03.062

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Highlights

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Rolipram improves cognition, reduces anxiety- and despair-like behaviors after BCCAO.

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Rolipram decreases hippocampal neurodegeneration induced by BCCAO.

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Rolipram increases DCX- and MAP-2 expression in the hippocampus of BCCAO mice.

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Abstract

Cognitive impairment, anxiety- and depressive-like symptoms are well recognized outcome of cerebral ischemia in clinical and preclinical settings. Rolipram, a phosphodiesterase-4 (PDE-4) inhibitor, improves cognition and produces anxiolytic- and antidepressant-like effects in rodents. Rolipram also exerts anti-inflammatory effects and enhances survival of newborn hippocampal neurons in mice subjected to transient global cerebral ischemia. Here, we evaluated the effects of chronic rolipram treatment in mice subjected to transient global brain ischemia. C56B6/7 mice were subjected to bilateral common carotid artery occlusion (BCCAO) and were then tested in a multi-tiered behavioral battery including the elevated zero maze (EZM), open field (OF), object location test (OLT), and forced swim test (FST). We also investigated the effects of rolipram on hippocampal neurodegeneration and the expression of the neuronal plasticity markers doublecortin (DCX) and microtubule-associated protein (MAP-2). Ischemic mice exhibited memory deficits OLT, higher levels of anxiety EZM and behavioral despair FST. BCCAO caused neuronal loss in the CA3 hippocampal subfield and basolateral amygdala (BLA). In the hippocampus of BCCAO mice, a disrupted neuronal plasticity was evidenced by decreased DCX expression. Chronic treatment with rolipram attenuated the behavioral effects of BCCAO. Rolipram also decreased neurodegeneration in the CA3 while it increased dendritic arborization of DCX-immunoreactive (DCX-IR) neurons and microtubule associate MAP-2 expression in the hippocampus of BCCAO mice. These data suggest that chronic inhibition of PDE-4 can be a useful therapeutic strategy to improve the emotional and cognitive outcomes of transient global cerebral ischemia.

Abbreviations

• BCCAO, bilateral common carotid artery occlusion;
• BLA, basolateral amygdala;
• cAMP, cyclic adenosine monophosphate;
• CREB, cAMP-responsive element binding protein;
• DAB, 3-3′-diaminobenzidine;
• DCX, doublecortin;
• DCX-IR, DCX-immunoreactive;
• EZM, elevated zero maze;
• FST, forced swim test;
• GCL, granular cell layer;
• MAP-2, microtubule-associated protein;
• MAP-2, microtubule-associated protein;
• OF, open field;
• OLT, object location test;
• PDE-4, phosphodiesterase-4;
• PKA, protein kinase A;
• SGZ, subgranular zone

Key words

• rolipram;
• bilateral common carotid artery occlusion;
• neuroprotection

Corresponding author. Tel: +55-44-30115165; fax: +55-44-30114999.

Copyright © 2016 Published by Elsevier Ltd.

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Improving Brain’s Garbage Disposal May Slow Alzheimer’s Disease

We need this and soon. But because we have NO stroke leadership or strategy nothing will get done on this.
Your 33% dementia chance post-stroke from an Australian study?  May 2012.
Then this study came out and seems to have a range from 17-66%. December 2013.
A 20% chance in this research.   July 2013.
http://medicalxpress.com/news/2015-01-scientists-heart-disease-clues-alzheimer.html

 Improving Brain’s Garbage Disposal May Slow Alzheimer’s Disease

A drug that boosts activity in the brain’s “garbage disposal” system can decrease levels of toxic proteins associated with Alzheimer’s disease and other neurodegenerative disorders and improve cognition in mice, a new study by neuroscientists at Columbia University Medical Center (CUMC) and New York State Psychiatric Institute (NYSPI) has found. The study was published today in the online edition of Nature Medicine.

“We have identified a new way to activate the brain’s garbage disposal system, and have shown that we can effectively use a drug to activate this system and slow down disease in a mouse model,” said study leader Karen E. Duff, PhD, professor of pathology and cell biology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at CUMC and NYSPI. “This has the potential to open up new avenues of treatment for Alzheimer’s and many other neurodegenerative diseases.”
The drug used was rolipram, which causes nausea and thus is not a good drug for use in humans. However, similar drugs do not incur nausea as a side effect and can be potentially tested in clinical trials quickly.
To remain healthy, brain cells must continually clear out old, worn, or damaged proteins, a task performed by a small molecular cylinder called the proteasome. The proteasome acts as a kind of garbage disposal, grinding up the old proteins so they can be recycled into new ones. In neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, proteins tagged for destruction accumulate in the brain’s neurons, suggesting that the cell’s proteasomes are impaired.
Using a genetically engineered mouse, the researchers first discovered that tau—a protein that accumulates in Alzheimer’s, frontotemporal degeneration, and other brain diseases—sticks to the proteasome and slows down the protein disposal process.
“Something profoundly bad happens to proteasomes in diseases where abnormal proteins accumulate,” said the study’s first author, Natura Myeku, PhD, an associate research scientist in the pathology and cell biology department at CUMC. “Our work on tau showed that even when proteasomes are removed from the diseased brains they remain defective and can’t chew up proteins compared with proteasome from normal brains.”
Administering rolipram activated the proteasome and restored protein disposal. The drug also improved memory in diseased mice to levels seen in healthy mice.
Rolipram has been tested before in mice, and was shown to improve memory. But the new research shows a previously unknown function of the drug that produces a physical change in the proteasome and increases its activity.
“We have uncovered a mechanism by which we can activate proteasomes,” said Dr. Myeku. “However, we still don’t have a full picture how those changes cause proteasomes to become super proteasomes that are able to remove toxic proteins from the brain. For now, it’s exciting to know that brain proteasomes can be repaired, which will allow us to develop better drugs.”
Drugs that target proteasomes in this way should work for any neurodegenerative disease caused by the accumulation of abnormal proteins, including Alzheimer’s, frontotemporal degeneration, Huntington’s, and Parkinson’s.
Dr. Duff noted, “Even though much work has been done, we still don’t know exactly which form of a particular protein is toxic to the brain. This has made it difficult to develop drugs to treat neurodegenerative diseases. In Alzheimer’s disease, the problem is compounded because several types of abnormal protein can accumulate in a person’s brain, including amyloid, tau, alpha-synuclein, and TDP43. We think that a well-functioning proteasome will be able to clear out everything at once.”
“This exciting research from Dr. Duff’s team advances our basic understanding of the proteasome system, provides a way to repair the system when it breaks, and holds the potential to alleviate symptoms of neurodegenerative disorders,” said Rod Corriveau, PhD, program director at the National Institute of Health’s National Institute of Neurological Disorders and Stroke, which provided funding for the study.
About the paper:
The study is titled, “Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.” The other contributors are: Catherine L. Clelland (CUMC), Sheina Emrani (CUMC), Nikolay V. Kukushkin (Harvard Medical School), Wai Haung Yu (CUMC) and Alfred L. Goldberg (Harvard Medical School).
The study was supported by grants from the National Institute of Neurological Disorders and Stroke (NS074593), the CurePSP Foundation, the National Institute of General Medical Sciences (GM051923), the Fidelity Biosciences Research Initiative, and the Multiple Myeloma Research Foundation.

The researchers declare no financial or other conflicts of interest.

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.