Category: Alzheimer’s

A new target for the prevention of adverse immune responses identified as factors in the development of Alzheimer's disease (AD) has been discovered by researchers at the University of South Florida's Department of Psychiatry and the Center of Excellence for Aging and Brain Repair.

Their findings are published online in the Journal of Neuroscience.

The CD45 molecule is a receptor on the surface of the brain's microglia cells, cells that support the brain's neurons and also participate in brain immune responses.

Previous studies by the USF researchers showed that triggering CD45 was beneficial because it blocked a very early step in the development of Alzheimer's disease. In the present study, the researchers demonstrated in Alzheimer's mouse models that a loss of CD45 led to dramatically increased microglial inflammation.

Although the brain's immune response is involved in Alzheimer's disease pathology, "this finding suggests that CD45 on brain immune cells appears critically involved in dampening harmful inflammation," said study senior author Jun Tan, MD, PhD, a professor of psychiatry and Robert A. Silver chair at the Rashid Laboratory for Developmental Neurobiology, USF Silver Child Development Center and research biologist for Research and Development Service at the James A. Haley Veteran's Hospital.

The investigators also found an increase in harmful neurotoxins, such as A beta peptides, as well as neuron loss in the brains of the test mice.

"In short, CD45 deficiency leads to increased accumulation of neurotoxic A beta in the brains of old Alzheimer's mice, demonstrating the involvement of CD45 in clearing those toxins and protecting neurons," Dr. Tan said. "These findings are quite significant, because many in the field have long considered CD45 to be an indicator of harmful inflammation. So, researchers assumed that CD45 was part of the problem, not a potential protective factor."

The next step is to apply these findings to develop new Alzheimer's disease treatments, said Paula Bickford, PhD, a professor in the USF Department of Neurosurgery and senior career research scientist at the James A. Haley Veteran's Hospital.

"We are already working with Natura Therapeutics, Inc. to screen for natural compounds that will target CD45 activation in the brain's immune cells," Dr. Bickford said.

Other researchers involved in this study were: Dr. Yuyan Zhu, Dr. Huayan Hou, Dr. Kavon Rezai-zadeh, Dr. Brian Giunta, Ms. Amanda Ruscin, Dr. Carmelina Gemma, Dr. JingJi Jin, Dr. Natasa Dragicevic, Dr. Patrick Bradshaw, Dr. Suhail Rasool, Dr. Charles G. Glabe (University of California, Irvine, CA), Dr. Jared Ehrhart, Dr. Takashi Mori (Saitama Medical Center/Saitama Medical University, Japan), Dr. Demian Obregon, Dr. Terrence Town (Cedars-Sinai Medical Center, Los Angeles, CA). Drs. Yuyan Zhu and Huayan Hou contributed equally to this work.

Their work was supported by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

 Misaligned research, medical challenges and harsh economics are thwarting efforts to slow the destructive course of Alzheimer's disease in the United States, according to a trio of nationally regarded Alzheimer's researchers writing a "Perspective" in the Jan. 27, 2011 issue of the journal Neuron.

The foremost obstacle is that the most promising preventive strategies are being tested in patients firmly in the grip of Alzheimer's disease — the ones least likely to be helped.

The approach would be similar to testing statins — drugs widely used to prevent heart disease — in patients who are already in cardiac arrest, according to Dr. Todd Golde, director of the UF College of Medicine's Center for Translational Research in Neurodegenerative Disease.

With Dr. Edward Koo of the University of California, San Diego, and Dr. Lon S. Schneider of the Keck School of Medicine at the University of Southern California, Golde pointed to a lack of alignment between studies in human volunteers, which focus on treatment, and preclinical laboratory studies, which are aimed at prevention.

"If we do the right types of clinical studies, we have the ability to move toward prevention, which would have a huge impact on this disease," said Golde, a professor in the department of neuroscience at UF's McKnight Brain Institute. "But we have to overcome our 'prevention versus treatment' dilemma. We already have more than 5 million people affected, and half of people in nursing homes, or more, have Alzheimer's disease. As society ages, we are just going to continue to see Alzheimer's drain the economy and the quality of human life."

Without medical breakthroughs, a projected 7.7 million patients in the U.S. will have Alzheimer's by 2030, according to the Alzheimer's Association. That number will grow to between 11 million and 16 million by 2050.

Researchers say solving the treatment-prevention problem will require the development of biomarkers — substances in the body that point to a disease — to identify patients before they show the symptoms associated with Alzheimer's. With biomarkers, it may be possible to test Alzheimer's drugs in pre-symptomatic volunteers.

"The dilemma is, can you treat people as if they have Alzheimer's if they do not?" said Koo, co-director of the Shiley-Marcos Alzheimer's Disease Research Center at UC San Diego. "That's the catch-22."

Most proposed Alzheimer's disease therapies target so-called "brain plaques" — proteins that clog the spaces between brain cells. Experimental models suggest that therapies targeting these proteins, known as amyloid beta-peptide, may be effective.

Approximately 90 experimental therapies intended to slow or stop the progression of the disease are under way, many of them targeting Alzheimer's hallmark brain plaques, according to the Alzheimer's Association. The problem is the strategies are likely to be much less effective when tested in patients who are already experiencing confusion, memory loss or personality changes.

But simply placing more emphasis on prevention has its own complications, the researchers say. To date, no drug candidates have been found to be effective at prevention or suitably safe enough for a patient to take for a lifetime.

And even if such a drug were found, clinical testing would take well more than a decade and cost pharmaceutical companies millions of dollars. If the drug were successful — and there is no guarantee — the company's patent would expire before it had a chance to recover its expenses.

"It is important to find ways to ensure that the commercial sector will invest in prevention trials that may take 10 years or more to complete," Koo said.

The authors said they are not the first to point out misalignment between clinical and preclinical studies, or summarize current therapeutics, or critique how trials are conducted.

But by presenting the issues in a comprehensive way, they hope to spur discussion among members of the research community, pharmaceutical companies and regulatory bodies to address the challenges.

"What we've done is collect those points and suggest what has to happen to help patients who are suffering from this awful disease," Golde said.

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Journal Reference:

1. Todd E. Golde, Lon S. Schneider, Edward H. Koo. Anti-Aβ Therapeutics in Alzheimer's Disease: The Need for a Paradigm Shift. Neuron, 2011; 69 (2): 203-213 DOI: 10.1016/j.neuron.2011.01.002

Mutant presenilin is infamous for its role in the most aggressive form of Alzheimer's disease — early-onset familial Alzheimer's — which can strike people as early as their 30s. In their latest study, researchers at the Salk Institute uncovered presenilin's productive side: It helps embryonic motor neurons navigate the maze of chemical cues that pull, push and hem them in on their way to their proper targets. Without it, budding motor neurons misread their guidance signals and get stuck in the spinal cord.

By putting genes associated with Alzheimer's disease in a new light, their findings, published in the Jan. 7, 2011, issue of the journal Cell, reveal an important link between the formation of neural circuits and neurodegenerative disorders. "It was a bit of a surprise since we always thought about presenilin in the context of severing neuronal connections rather than wiring the nervous system during embryonic development," says Howard Hughes Medical Institute investigator Samuel Pfaff, Ph.D., a professor in the Gene Expression Laboratory, who led the study.

Presenilin is a component of the enzyme gamma secretase, which cleaves the amyloid precursor protein, resulting in accumulation of beta amyloid fragments. In Alzheimer's, these fragments form hard, insoluble plaques, one of the hallmarks of the disease.

Many embryonic guidance molecules persist in the adult central nervous system, where they participate in maintenance, repair and plasticity of neural circuits. "This could explain how a deregulation of guidance signaling by abnormal presenilin may play a role in the pathogenesis of Alzheimer's disease," proposes Pfaff.

The Salk study also adds an important new piece to the clockwork mechanism that guides growing nerve cells through the embryo and that depends as much on timing as on spatial accuracy. Understanding how axons find their destinations may help restore movement in people following spinal cord injury, or in those with motor neuron diseases such as Lou Gehrig's disease, spinal muscle atrophy and post-polio syndrome.

During normal development, trillions of neurons reach out for others with long, slender extensions to touch, connect and wire the budding nervous system. As the hair-like protrusions, called axons, grope around in the developing embryo, trying to find their proper targets, molecular ushers stationed along their path steer them in the right direction.

"Because of the vast number of neurons in the nervous system, ensuring that every single cell is on target creates more biological complexity than we can account for with the genetic information encoded in our genome," says Pfaff. "There are an estimated 100 trillion connections in our brain and only about 20,000 genes."

To find their course, growing neurons, especially motor neurons, which need to travel very long distances to reach their targets, navigate their path one small segment at a time, guided at each intersection by intermediate guideposts — chemical cues that attract or repel approaching axons. What's more, in a tightly regulated choreography, axons often switch allegiances when they reach a critical junction.

"It provides a way of creating some of these intermediate temporal steps," explains postdoctoral researcher and first author Ge Bai. "It allows the use of a small number of genes to regulate axonal growth by regulating the signals' effects in a very precise temporal and spatial ways."

He and his team found presenilin's unexpected role in controlling the activity of axon guidance signals during a search for genes involved in the fetal development of the nervous system. They had developed a method of engineering mice so that all of their motor neurons glow green. This fluorescence allowed them to visually identify mutant mice that have errors in motor neuron development and function.

One mouse, whose specific defect the researchers had mapped to the gene coding for presenilin, stood out. Failing to exit the spinal cord, its motor neurons got stuck at the midline, a row of cells that lie, moat-like, in the middle of the developing embryo. Bai discovered that in presenilin mutant mice, they were irresistibly attracted to Netrin, which is expressed by the midline.

In normal mice, motor neurons turn a deaf ear to Netrin's siren call and head out to the periphery. They are able to ignore Netrin because the receptor for Netrin is blocked by the so-called Slit/Robo tag team. Without presenilin, however, Netrin receptor fragments that are resistant to Slit/Robo silencing accumulate in the cell, and the motor neurons are now attracted to Netrin.

"The most satisfying thing we have learned about presenilin is that this is a component that is not directly involved in the detection of signals either as a ligand or a receptor but functions as a very important regulator of their spatiotemporal activity," says Bai.

Researchers who also contributed to the work include Onanong Chivatakarn, Dario Bonanomi, Karen Lettieri, and Laura Franco at the Salk Institute; Caihong Xia and Le Ma at the Zilkha Neurogenetic Institute at the University of of Southern California in Los Angeles; Elke Stein in the Department of Molecular, Cellular and Developmental Biology at Yale University, New Haven, CT; and Joseph W. Lewcock, formerly a postdoc in the Pfaff lab and now in the Department of Neurobiology at Genentech, San Francisco.

The work was funded in part by the Howard Hughes Medical Institute and the National Institutes of Health.

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Journal Reference:

1. Ge Bai, Onanong Chivatakarn, Dario Bonanomi, Karen Lettieri, Laura Franco, Caihong Xia, Elke Stein, Le Ma, Joseph W. Lewcock, Samuel L. Pfaff. Presenilin-Dependent Receptor Processing Is Required for Axon Guidance. Cell, 2011; 144 (1): 106-118 DOI: 10.1016/j.cell.2010.11.053

Researchers at the University of North Carolina at Chapel Hill have discovered a molecule that can make brain cells resistant to programmed cell death or apoptosis.

This molecule, a tiny strand of nucleotides called microRNA-29 or miR-29, has already been shown to be in short supply in certain neurodegenerative illnesses such as Alzheimer's disease and Huntington's disease. Thus, the discovery could herald a new treatment to prompt brain cells to survive in the wake of neurodegeneration or acute injury like stroke.

"There is the real possibility that this molecule could be used to block the cascade of events known as apoptosis that eventually causes brain cells to break down and die," said senior study author Mohanish Deshmukh, PhD, associate professor of cell and developmental biology.

The study, published online Jan. 18, 2011, in the journal Genes & Development, is the first to find a mammalian microRNA capable of stopping neuronal apoptosis.

Remarkably, a large number of the neurons we are born with end up dying during the normal development of our bodies. Our nerve cells must span great distances to ultimately innervate our limbs, muscles and vital organs. Because not all nerve cells manage to reach their target tissues, the body overcompensates by sending out twice as many neurons as required. The first ones to reach their target get the prize, a cocktail of factors needed for them to survive, while the ones left behind die off. Once that brutal developmental phase is over, the remaining neurons become impervious to apoptosis and live long term.

But exactly what happens to suddenly keep these cells from dying has been a mystery. Deshmukh thought the key might lie in microRNAs, tiny but powerful molecules that silence the activity of as many as two-thirds of all human genes. Though microRNAs have been a hotbed of research in recent years, there have been relatively few studies showing that they play a role in apoptosis. So Deshmukh and his colleagues decided to look at all of the known microRNAs and see if there were any differences in young mouse neurons versus mature mouse neurons.

One microRNA jumped out at them, an entity called miR-29, which at that time had never before been implicated in preventing apoptosis. When the researchers injected their new molecule into young neurons, which are able to die if instructed, they found that the cells became resistant to apoptosis, even in the face of multiple death signals.

They then decided to pinpoint where exactly this molecule played a role in the series of biochemical events leading to cell death. The researchers looked at a number of steps in apoptosis and found that miR-29 acts at a key point in the initiation of apoptosis by interacting with a group of genes called the BH3-only family. Interestingly, the microRNA appears to interact with not just one but as many as five members of that family, circumventing a redundancy that existed to allow cell death to continue even if one of them had been blocked.

"People in the field have been perplexed that when they have knocked-out any one of these members it hasn't had a remarkable effect on apoptosis because there are others that can step in and do the job," said Deshmukh. "The fact that this microRNA can target multiple members of this family is very interesting because it shows how a single molecule can basically in one stroke keep apoptosis from happening. Interestingly, it only targets the members that are important for neuronal apoptosis, so it may be a way of specifically preserving cells in the brain without allowing them to grow out of control (and cause cancer) elsewhere in the body."

Deshmukh is currently developing mouse models where miR-29 is either "knocked-out" or overactive and plans to cross them with models of Alzheimer's disease, Parkinson's disease and ALS to see if it can prevent neurodegeneration. He is also actively screening for small molecule compounds that can elevate this microRNA and promote neuronal survival.

The research was funded by the National Institutes of Health. Study co-authors were Adam J. Kole, a graduate student in Deshmukh's lab; Vijay Swahari, research technician; and Scott M. Hammond, PhD, associate professor of cell and developmental biology..

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Journal Reference:

1. A. J. Kole, V. Swahari, S. M. Hammond, M. Deshmukh. miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis. Genes & Development, 2011; 25 (2): 125 DOI: 10.1101/gad.1975411

 A study by researchers at Mayo Clinic's campus in Florida and Washington University School of Medicine adds a new twist to the body of evidence suggesting human obesity is due in part to genetic factors. While studying hormone receptors in laboratory mice, neuroscientists identified a new molecular player responsible for the regulation of appetite and metabolism.

In the Jan. 11 online issue of PLoS Biology, the authors report that mice engineered not to express the lipoprotein receptor LRP1, in the brain's hypothalamus, began to eat uncontrollably, growing obese as well as lethargic. They found that LRP1, a major transporter of lipids and proteins into brain cells, is a "co-receptor" with the leptin receptor — meaning that both the leptin and LRP1 receptors need to work together to transmit leptin signals.

Leptin decides whether fat should be stored or used, resulting in lethargy or energy. When working properly, the hormone, which is made when body cells take in fat from food, travels to the brain to tamp down appetite.

"If a person is born with too little gene expression in the leptin pathway, which includes its receptors, or the circuitry is not functioning well, then leptin will not work as well as it should," says the study's lead investigator, neuroscientist Guojun Bu, Ph.D., of Mayo Clinic. "Appetite will increase, and body fat will be stored."

Given these results, Dr. Bu says it may be possible to develop a treatment that increases gene expression in one or both of the protein receptors, which then increases the messages meant to decrease appetite sent to the brain.

The serendipitous findings were born out of Dr. Bu's primary research focus, Alzheimer's disease. He has been studying how cholesterol, essential to the smooth functioning of neurons, is carried from star-shaped astrocytes to the surface of neurons by apolipoprotein E (APOE). There are two major receptors for APOE on brain neurons, and LRP1 is one of them.

Inheriting one version of APOE — APOE4 — is a known risk factor for development of Alzheimer's disease, and Dr. Bu has found that APOE4 is less effective at transporting cholesterol. To understand what role LRP1 plays in bringing APOE4 into neurons, he created a knockout mouse model with no expression of LRP1 in its forebrain neurons; the rest of its body expressed the receptor normally.

He found neurons lacking LRP1 had even less ability to absorb cholesterol, and that they lost synaptic contact with other neurons, impairing their ability to retain memory.

But Dr. Bu was surprised to find the mice suddenly gained weight. "This is the opposite of what had been observed in mice who did not have the receptor in their body fat cells," he says. "Those animals became skinny because they couldn't absorb enough lipoproteins."

The knockout mice were indistinguishable from control mice for the first six months of life but then gained weight rapidly, a phenomenon that correlated with a decrease in LPR1 expression in the central nervous system. At 12 months old, the genetically engineered mice had twice as much body fat as control mice, lacked energy, and were insulin resistant. "Together, these results indicate that LRP1, which is critical in lipid metabolism, also regulates food intake and energy balance in the adult central nervous system," Dr. Bu says.

The study was funded by the National Institutes of Health and the Alzheimer's Association.

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Journal Reference:

1. Qiang Liu, Juan Zhang, Celina Zerbinatti, Yan Zhan, Benedict J. Kolber, Joachim Herz, Louis J. Muglia, Guojun Bu. Lipoprotein Receptor LRP1 Regulates Leptin Signaling and Energy Homeostasis in the Adult Central Nervous System. PLoS Biology, 2011; 9 (1): e1000575 DOI: 10.1371/journal.pbio.1000575