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ENSAYOS Y ARTICULOS

miércoles, 26 de diciembre de 2012

ALZHEIMER : NUEVAS INVESTIGACIONES

New Research on Alzheimer Treatments Ventures Beyond Plaques and Tangles
M. J. Friedrich
JAMA. 2012;308(24):2553-2555.

New Orleans—Despite decades of research on treatments for Alzheimer disease (AD), no therapies have been found to prevent, halt, or reverse this neurodegenerative disorder, which affects about 5.4 million people in the United States alone.
.That's not for lack of trying, said Lennart Mucke, MD, PhD, director of the Gladstone Institute of Neurological Disease at the University of California, San Francisco, who spoke at the annual meeting of the Society for Neuroscience. While research is contributing to a better understanding of the disease, these mechanistic insights haven't yet translated into successful therapies, he said.
.A number of factors may contribute to the failure of AD therapeutics in clinical trials. One possibility is that the drugs are initiated when the disease has progressed too far to be reversed, said Ottavio Arancio, MD, PhD, of Columbia University, New York City. Alzheimer disease may begin decades before it can be detected, so moving toward early detection and initiation of treatment may be an important goal, he said.
In a healthy brain, microglial cells and astrocytes release molecules that keep the brain running smoothly. In Alzheimer disease, microglia and astrocytes can become dysregulated, causing detrimental neuroinflammation that can promote the development and progression of neurodegeneration.
.Another possibility is that the drugs that have been developed for AD do not zero in on the pathways that are crucial to the development of the disease. Two key features of AD in the brain—plaques of amyloid-β peptides and neurofibrillary tangles consisting of tau protein—combine to block communication between neurons and disrupt their survival. Plaques and tangles are thought to play a causal role in the pathogenesis of the disease, but the underlying mechanisms of AD pathogenesis remain uncertain. “There are many unresolved questions about how you get from these pathogenic proteins to the actual dysfunction and degeneration of neurons or glial cells,” said Mucke.
.Other aspects of the disease are equally important, although not as well understood. “There is clearly a need to diversify our therapeutic approaches,” said Arancio. At the neuroscience meeting, researchers discussed a number of novel strategies that go beyond specific targeting of plaques or tangles.
.INSULIN RESISTANCE IN THE BRAIN.

INSULIN RESISTANCE IN THE BRAIN
PUTTING INSULIN IN THE BRAIN
MIMICKING APOE3 ...Growing evidence about insulin's important role in normal brain function and cognition points to a new avenue for treating AD.
.Low levels of insulin and reduced insulin activity in the brain are associated with cognitive impairment and AD, and people with type 2 diabetes have double the risk of developing AD compared with people whose blood glucose levels are normal. Insulin also has a close relationship with the amyloid-β peptide: it modulates the levels of amyloid β and protects against the detrimental effects of amyloid-β oligomers on neuronal synapses. This association has led researchers to explore how insulin dysregulation in the brain may contribute to the development of AD.
.Insulin at optimal levels in the brain is protective, enhances memory, and facilitates plasticity, but levels that are too low or too high can cause problems. If the brain's ability to respond to insulin goes awry, it can become resistant to the positive effects of insulin. Some researchers refer to this insulin resistance as a brain-specific form of diabetes.
.It is important to note that insulin acts differently in the brain than it does in the rest of the body, said Konrad Talbot, PhD, of the University of Pennsylvania, Philadelphia, and that there is no evidence that the brains of patients with AD have high blood glucose levels, as is true of the peripheral tissues of a patient with diabetes. Therefore, an individual doesn't need to have type 2 diabetes to develop insulin resistance in the brain, although it often does arise in people with type 2 diabetes or peripheral insulin resistance.
.Konrad and his colleagues found that insulin resistance in the brain contributes to cognitive decline and is a common and early feature of AD. Examining postmortem brain tissue from people who did not have type 2 diabetes but had died with AD, Konrad's team identified defects in 2 major signaling pathways in the brain for insulin and insulin-like growth factor (Talbot K et al. J Clin Invest. 2012;122[4]:1316-1338).
.Targeting these pathways with drugs that help resensitize the brain to insulin might help slow cognitive decline or improve cognitive function. One promising candidate is a new class of diabetes drugs called glucagon-like peptide-1 (GLP-1) receptor agonists; these compounds mimic the hormone GLP-1, which helps the body produce insulin. One such drug, liraglutide, has been shown to reduce amyloid production and protect neurons from amyloid damage.
.In unpublished studies, Konrad's group tested liraglutide in a mouse model of AD and found that it alleviated brain insulin resistance in the animals. Another group, led by Fernanda De Felice, PhD, of the Federal University of Rio de Janeiro, Brazil, showed that a similar drug, exendin-4, normalized insulin signaling and improved cognitive function in a mouse model of AD (Bomfim TR et al. J Clin Invest. 2012;122[4]:1339-1353).
.PUTTING INSULIN IN THE BRAIN.
INSULIN RESISTANCE IN THE BRAIN
PUTTING INSULIN IN THE BRAIN
MIMICKING APOE3 ...Using insulin itself delivered directly to the brain to restore normal insulin function is another promising strategy. In a 4-month pilot study involving 104 participants with mild cognitive impairment and mild to moderate AD, researchers at the University of Washington, Seattle, led by Suzanne Craft, PhD, now of Wake Forest Baptist Medical Center, Winston-Salem, NC, used a noninvasive intranasal device to deliver insulin deep within the nose; from there, it travels to the brain. They found that the treatment improved memory, cognition, and daily functioning with no severe adverse events reported (Craft S et al. Arch Neurol. 2012;69[1]:29-38).
.Craft and her colleagues plan to test the treatment in a large multisite trial that will begin in April 2013 and last 5 years. The study, part of the National Alzheimer Project Act signed by President Barack Obama last year, will recruit 240 volunteers for a year-long treatment trial at many sites across the United States.
.Another novel strategy for treating AD involves targeting neuroinflammation. In a healthy brain, glial cells—primarily the microglia and astrocytes—produce and release molecules that keep the brain running smoothly. In neurodegenerative disorders, glial cells can become dysregulated, with the normal beneficial inflammation responses going awry and causing a state of detrimental neuroinflammation that can promote the development and progression of neurodegeneration.
.Linda Van Eldik, PhD, of the University of Kentucky, Lexington, and her colleagues have focused efforts on down-regulating neuroinflammation to treat AD. They developed a small molecule that selectively inhibits proinflammatory cytokine overproduction in glial cells by targeting intracellular signaling pathways in the astrocytes and microglia, primarily protein kinase–regulated pathways. These pathways lead to neurodegenerative disease or injury-induced up-regulation of proinflammatory cytokines such as interleukin 1 and tumor necrosis factor.
.Van Eldik's group showed that in mouse models of AD, as well as in other animal models of central nervous system disorders, this oral compound, MW151, blocks the detrimental proinflammatory responses but not the anti-inflammatory responses and also prevents the loss of synaptic proteins.“At least in this AD model, you see beneficial effects without affecting amyloid β, which doesn't mean that amyloid β isn't important, but it does show that these activities can be uncoupled,” she said.
.The compound is effective when given either early or late in disease progression in animal models, but it seems much more effective when given in a preventive mode, said Van Eldik. “It may be that targeting neuroinflammation needs to be done early in the disease,” she said.
.Van Eldik noted that her group has developed a variety of novel and orally administered drugs that easily cross the blood-brain barrier, and a related second-generation drug has entered human trials and gone through a phase 1 ascending-dose trial with no adverse events.
.MIMICKING APOE3.

INSULIN RESISTANCE IN THE BRAIN
PUTTING INSULIN IN THE BRAIN
MIMICKING APOE3 ...Another approach for tamping down inflammation in the brain is to develop drugs that mimic apolipoprotein E (ApoE), the lipid-carrier molecule that in one of its forms is the risk factor most commonly associated with sporadic AD.
.The human genome contains multiple alleles of the APOE gene that encode different ApoE protein isoforms, with ApoE2, ApoE3, and ApoE4 being the most common. One in 6 people in the general population carries the ApoE4 allele, but half to three-quarters of patients with AD carry ApoE4.
.ApoE4 does not cause AD, but it does lead to an increased susceptibility for the disease. Those who inherit 1 or 2 copies of the ApoE4 allele are at a greater risk of developing AD and may do so at a younger age, although not all ApoE4 carriers develop AD. ApoE4 is also associated with a number of other neurodegenerative conditions. Conversely, ApoE3 seems to have a protective effect.
.Michael Vitek, PhD, of Duke University Medical Center, Durham, NC, and his colleagues hypothesized that ApoE3 suppresses inflammation more than ApoE4 and thereby confers protection from many neurodegenerative conditions, including AD, that are marked by inappropriate inflammation in the brain.
.Despite ApoE4's influence on risk for AD, few therapeutic strategies aimed at this protein have made it to clinical trials. Vitek discussed compounds that mimic the anti-inflammatory properties of ApoE3 that he and his colleagues developed at a biotech company, Cognosci, Research Triangle Park, NC, which he founded. The compounds are short peptides that correspond to an area of ApoE3.
.Vitek's group has shown that the prototype of these compounds, COG133, reduced inflammatory responses in human blood ex vivo and also in the central nervous system and the periphery of mice treated with lipopolysaccharide, which promotes inflammation.
.In transgenic mouse models of AD, animals that received the ApoE3 mimetics COG112 and COG1410 madeless of the proinflammatory cytokine interleukin 6, lost fewer neurons, and grew fewer plaques and neurofibrillary tangles; they also showed improvement in learning and memory compared with untreated mice (Vitek MP et al. Neurodegener Dis. 2012;10[1-4]:122-126), suggesting that these drugs may represent a new class of therapeutics for AD.
.Gladstone's Mucke concluded that as with other multifactorial diseases, AD will likely need to be treated with a combination of drugs.
.“Ultimately, we will probably need a toolbox with drugs targeted not only to amyloid β but to many other factors that contribute to the cognitive dysfunction seen in AD—an approach that will require an increased interdisciplinary attack on this condition,” Mucke said.

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