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Studio del 2006 sul morbo di Alzheimer.
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Studio del 2006 sul morbo di Alzheimer. è stato creato da lucadoc
[size=12pt]Alzheimer's disease: new mechanisms for an old problem[/size]
by Robert G. Nagele
Alzheimer’s disease (AD) is a devastating, aging-associated, neurodegenerative disorder that produces a dramatic and
progressive decline in learning and memory. As many as four million Americans currently suffer from AD and, in view of the projected increase in average lifespan, failure to effectively prevent or treat this disease will result in a more than three-fold increase in its incidence within the next few decades. Studies being carried out in our laboratory at the New Jersey Institute for Successful Aging (NJISA) in Stratford have focused on elucidating mechanisms that drive the deposition of amyloid protein in the brain tissue of patients afflicted with this disease, a process that has been linked to memory and cognitive decline. The high incidence of blood-brain barrier breakdown in AD patients along with the common presence of neuron-binding autoantibodies and soluble amyloid peptides in human serum have opened up new therapeutic opportunities that have the potential to slow or halt disease progression.
AD evolves with widespread loss of neurons and their synapses in such key brain areas as the cerebral cortex, entorhinal area, and hippocampus. At the gross level, this is evident as a general shrinkage of the brain away from the cranial vault and a corresponding dilation of the fluid-filled brain ventricles to fill the void. At the microscopic level, there are several different pathological changes that occur, but one consistent pathological hallmark is the early appearance of amyloid plaques. These plaques are abundant and widely scattered throughout AD-vulnerable brain regions. They contain a 42-amino acid protein fragment, known as amyloid β1-42 (Aβ42), that is derived from the sequential enzymatic cleavage of the much larger amyloid precursor protein. Once produced, Aβ42 has the ability to self-assemble into nondegradeable fibrils that can persist in AD brains long after the neurons in which they accumulated have died.
The mechanism by which Aβ42 is deposited within plaques has been under intense investigation for decades. Until recently, the prevailing theory was that plaques arise from a gradual deposition of Aβ42 at extracellular “seeding sites” in the brain tissue. However, during the past five years, results of studies carried out by our team (funded by the Alzheimer’s Association) and others have contested this dogma, instead showing that Aβ42 first accumulates within neurons prior to plaque formation, primarily targeting pyramidal neurons in the cerebral cortex and hippocampus. We have proposed that deposition of Aβ42 within vulnerable neurons progressively impairs the ability of these cells to maintain their normal structure and function. In the end, collapse of their dendrites and all-important synapses, the site where neurons communicate with one another, leads to the loss of cognition and memory that brings these patients into the doctor’s office as well as eventual neuronal death. We have found that when neurons overburdened with Aβ42 eventually die, they rupture and disperse their cytoplasmic contents (including accumulated Aβ42) into the surrounding area to form a single amyloid plaque. In this case, one can consider a single amyloid plaque to be a tombstone which marks the place in the brain that was previously occupied by a neuron.
With the focus of AD research shifting to events going on inside of neurons, new questions emerge that must be resolved before meaningful therapeutic targets aimed at blocking the initiation and slowing the progression of AD can be pursued. One such question is: What is the source of the Aβ42 that accumulates in neurons? Recent work carried out by Peter Clifford, a DO/PhD student in our laboratory at the NJISA, has investigated the possibility that the blood vessels, which contain Aβ42 at concentrations that are 10-fold higher than in the brain, chronically leak soluble Aβ42 into the brain tissue of AD patients through a defective blood-brain barrier. Our immunohistochemical analyses of AD and age-matched neurologically normal control brains have confirmed that soluble Aβ42 and a number of other plasma components constantly trickle into the brain tissue in AD patients, whereas the brains of normal healthy individuals are generally protected from this influx by virtue of the integrity of the blood-brain barrier.
To test whether blood-borne Ab peptides can cross a defective blood-brain barrier in living animals, we tracked the fate of fluorescent-tagged Aβ42 peptide introduced by means of tail vein injection into mice with a blood-brain barrier rendered permeable by exposure to pertussis toxin. Results showed that Aβ42 readily penetrated the defective blood-brain barrier, bound selectively to neurons, and accumulated within the same subtypes of neurons that are overburdened with large, intracellular Aβ42-rich deposits in human AD brains. In view of the high incidence of blood-brain barrier compromise in AD patients, these results increase the likelihood that the blood serves as a major, chronic source of the soluble, exogenous Aβ42 that accumulates within neurons and deposits within AD brains. If this proves to be the case, then therapeutic strategies aimed at lowering Aβ42 production and/or blood levels of Aβ42 may be effective in slowing disease progression.
Unfortunately, Aβ42 is not the only plasma component that enters into the brain tissue and shows a propensity for binding to the surfaces of neurons. Immunohistochemical and biochemical studies carried out by Gilbert Siu, another DO/PhD student in our laboratory at the NJISA, have led to the discovery that human serum commonly contains autoantibodies that can bind selectively to the surfaces of the same neurons that are known to accumulate excessive Aβ42 in the brains of AD patients.
We have thus far detected at least five potential antigen targets for these human autoantibodies in both mouse and human brain membrane protein fractions. Surprisingly, all of these autoantibodies also recognize and bind to double-stranded (ds) DNA and dsDNA/histone complex. One common protein target for these autoantibodies has been identified as the glutamate R2 (GluR2) subunit of the AMPA receptor complex, a portion of which is recognized by anti-dsDNA antibodies through molecular mimicry. Interestingly, the presence of this antibody has also been reported in elderly patients with systemic lupus erythematosus, who often exhibit an AD-like memory loss and cognitive decline. These findings have led us to hypothesize that (1) breakdown of the blood-brain barrier allows access of neuron-binding autoantibodies and soluble exogenous Aβ42 to brain neurons and (2) binding of these autoantibodies to neurons triggers and/or facilitates the internalization and accumulation of cell surface-bound Aβ42 in vulnerable neurons through their natural tendency to clear surface-bound autoantibodies via endocytosis.
In support of this possibility, we have shown that autoantibodies from individual human sera that intensely immunolabel neurons in sections of AD brain tissue also dramatically enhance the internalization of exogenous Aβ42 in neurons in vitro (in mouse brain slice cultures) and in vivo (in mouse brains receiving direct intracranial injections of human serum and Aβ42 peptide). These results suggest that individuals with high titers of specific neuron-binding autoantibodies may generally be more at risk for AD than are those lacking these autoantibodies. If so, then detection of specific antibody profiles in human serum may help to identify those at risk for AD and open up new possibilities for both early therapeutic intervention and treatment of those already afflicted. Our hope is that these results will spark the development of new therapeutic targets aimed at maintaining the integrity of the blood-brain barrier and/or reducing blood levels of disease-specific antineuronal autoantibodies and Aβ42, all of which may contribute to slowing disease progression or, better yet, circumventing this devastating disease altogether.
www.umdnj.edu/research/publications/fall06/4.htm
by Robert G. Nagele
Alzheimer’s disease (AD) is a devastating, aging-associated, neurodegenerative disorder that produces a dramatic and
progressive decline in learning and memory. As many as four million Americans currently suffer from AD and, in view of the projected increase in average lifespan, failure to effectively prevent or treat this disease will result in a more than three-fold increase in its incidence within the next few decades. Studies being carried out in our laboratory at the New Jersey Institute for Successful Aging (NJISA) in Stratford have focused on elucidating mechanisms that drive the deposition of amyloid protein in the brain tissue of patients afflicted with this disease, a process that has been linked to memory and cognitive decline. The high incidence of blood-brain barrier breakdown in AD patients along with the common presence of neuron-binding autoantibodies and soluble amyloid peptides in human serum have opened up new therapeutic opportunities that have the potential to slow or halt disease progression.
AD evolves with widespread loss of neurons and their synapses in such key brain areas as the cerebral cortex, entorhinal area, and hippocampus. At the gross level, this is evident as a general shrinkage of the brain away from the cranial vault and a corresponding dilation of the fluid-filled brain ventricles to fill the void. At the microscopic level, there are several different pathological changes that occur, but one consistent pathological hallmark is the early appearance of amyloid plaques. These plaques are abundant and widely scattered throughout AD-vulnerable brain regions. They contain a 42-amino acid protein fragment, known as amyloid β1-42 (Aβ42), that is derived from the sequential enzymatic cleavage of the much larger amyloid precursor protein. Once produced, Aβ42 has the ability to self-assemble into nondegradeable fibrils that can persist in AD brains long after the neurons in which they accumulated have died.
The mechanism by which Aβ42 is deposited within plaques has been under intense investigation for decades. Until recently, the prevailing theory was that plaques arise from a gradual deposition of Aβ42 at extracellular “seeding sites” in the brain tissue. However, during the past five years, results of studies carried out by our team (funded by the Alzheimer’s Association) and others have contested this dogma, instead showing that Aβ42 first accumulates within neurons prior to plaque formation, primarily targeting pyramidal neurons in the cerebral cortex and hippocampus. We have proposed that deposition of Aβ42 within vulnerable neurons progressively impairs the ability of these cells to maintain their normal structure and function. In the end, collapse of their dendrites and all-important synapses, the site where neurons communicate with one another, leads to the loss of cognition and memory that brings these patients into the doctor’s office as well as eventual neuronal death. We have found that when neurons overburdened with Aβ42 eventually die, they rupture and disperse their cytoplasmic contents (including accumulated Aβ42) into the surrounding area to form a single amyloid plaque. In this case, one can consider a single amyloid plaque to be a tombstone which marks the place in the brain that was previously occupied by a neuron.
With the focus of AD research shifting to events going on inside of neurons, new questions emerge that must be resolved before meaningful therapeutic targets aimed at blocking the initiation and slowing the progression of AD can be pursued. One such question is: What is the source of the Aβ42 that accumulates in neurons? Recent work carried out by Peter Clifford, a DO/PhD student in our laboratory at the NJISA, has investigated the possibility that the blood vessels, which contain Aβ42 at concentrations that are 10-fold higher than in the brain, chronically leak soluble Aβ42 into the brain tissue of AD patients through a defective blood-brain barrier. Our immunohistochemical analyses of AD and age-matched neurologically normal control brains have confirmed that soluble Aβ42 and a number of other plasma components constantly trickle into the brain tissue in AD patients, whereas the brains of normal healthy individuals are generally protected from this influx by virtue of the integrity of the blood-brain barrier.
To test whether blood-borne Ab peptides can cross a defective blood-brain barrier in living animals, we tracked the fate of fluorescent-tagged Aβ42 peptide introduced by means of tail vein injection into mice with a blood-brain barrier rendered permeable by exposure to pertussis toxin. Results showed that Aβ42 readily penetrated the defective blood-brain barrier, bound selectively to neurons, and accumulated within the same subtypes of neurons that are overburdened with large, intracellular Aβ42-rich deposits in human AD brains. In view of the high incidence of blood-brain barrier compromise in AD patients, these results increase the likelihood that the blood serves as a major, chronic source of the soluble, exogenous Aβ42 that accumulates within neurons and deposits within AD brains. If this proves to be the case, then therapeutic strategies aimed at lowering Aβ42 production and/or blood levels of Aβ42 may be effective in slowing disease progression.
Unfortunately, Aβ42 is not the only plasma component that enters into the brain tissue and shows a propensity for binding to the surfaces of neurons. Immunohistochemical and biochemical studies carried out by Gilbert Siu, another DO/PhD student in our laboratory at the NJISA, have led to the discovery that human serum commonly contains autoantibodies that can bind selectively to the surfaces of the same neurons that are known to accumulate excessive Aβ42 in the brains of AD patients.
We have thus far detected at least five potential antigen targets for these human autoantibodies in both mouse and human brain membrane protein fractions. Surprisingly, all of these autoantibodies also recognize and bind to double-stranded (ds) DNA and dsDNA/histone complex. One common protein target for these autoantibodies has been identified as the glutamate R2 (GluR2) subunit of the AMPA receptor complex, a portion of which is recognized by anti-dsDNA antibodies through molecular mimicry. Interestingly, the presence of this antibody has also been reported in elderly patients with systemic lupus erythematosus, who often exhibit an AD-like memory loss and cognitive decline. These findings have led us to hypothesize that (1) breakdown of the blood-brain barrier allows access of neuron-binding autoantibodies and soluble exogenous Aβ42 to brain neurons and (2) binding of these autoantibodies to neurons triggers and/or facilitates the internalization and accumulation of cell surface-bound Aβ42 in vulnerable neurons through their natural tendency to clear surface-bound autoantibodies via endocytosis.
In support of this possibility, we have shown that autoantibodies from individual human sera that intensely immunolabel neurons in sections of AD brain tissue also dramatically enhance the internalization of exogenous Aβ42 in neurons in vitro (in mouse brain slice cultures) and in vivo (in mouse brains receiving direct intracranial injections of human serum and Aβ42 peptide). These results suggest that individuals with high titers of specific neuron-binding autoantibodies may generally be more at risk for AD than are those lacking these autoantibodies. If so, then detection of specific antibody profiles in human serum may help to identify those at risk for AD and open up new possibilities for both early therapeutic intervention and treatment of those already afflicted. Our hope is that these results will spark the development of new therapeutic targets aimed at maintaining the integrity of the blood-brain barrier and/or reducing blood levels of disease-specific antineuronal autoantibodies and Aβ42, all of which may contribute to slowing disease progression or, better yet, circumventing this devastating disease altogether.
www.umdnj.edu/research/publications/fall06/4.htm
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