Journal of Biological Chemistry · 1998 · 163 citations · 30 references
Life SciencesNeurobiologyNeuroscienceInflammationMolecular NeuroscienceNeuroimmunologyAmino Acid NeurochemistryMicroglia BiologyNeurodegeneration MechanismsNeurodegenerative DiseasesNeuroinflammationNeuroprotectionAmyloid Beta PeptidesAmyloid Beta PlaquesAmyloid PlaquesAmyloid-beta-induced NeurotoxicityMicroglia ActivationMicroglial InteractionsNeuritic PlaquesNeuroinflammation In Alzheimer Disease
The β-amyloid peptide 1–42 (Aβ1–42), a major component of neuritic and core plaques found in Alzheimer's disease, activates microglia to kill neurons. Selective modifications of amino acids near the N terminus of Aβ showed that residues 13–16, the HHQK domain, bind to microglial cells. This same cluster of basic amino acids is also known as a domain with high binding affinity for heparan sulfate. Both Aβ binding to microglia and Aβ induction of microglial killing of neurons were sensitive to heparitinase cleavage and to competition with heparan sulfate, suggesting membrane-associated heparan sulfate mediated plaque-microglia interactions through the HHQK domain. Importantly, small peptides containing HHQK inhibited Aβ1–42 cell binding as well as plaque induction of neurotoxicity in human microglia. In vivo experiments confirmed that the HHQK peptide reduces rat brain inflammation elicited after infusion of Aβ peptides or implantation of native plaque fragments. Strategies which exploit HHQK-like agents may offer a specific therapy to block plaque-induced microgliosis and, in this way, slow the neuronal loss and dementia of Alzheimer's disease. The β-amyloid peptide 1–42 (Aβ1–42), a major component of neuritic and core plaques found in Alzheimer's disease, activates microglia to kill neurons. Selective modifications of amino acids near the N terminus of Aβ showed that residues 13–16, the HHQK domain, bind to microglial cells. This same cluster of basic amino acids is also known as a domain with high binding affinity for heparan sulfate. Both Aβ binding to microglia and Aβ induction of microglial killing of neurons were sensitive to heparitinase cleavage and to competition with heparan sulfate, suggesting membrane-associated heparan sulfate mediated plaque-microglia interactions through the HHQK domain. Importantly, small peptides containing HHQK inhibited Aβ1–42 cell binding as well as plaque induction of neurotoxicity in human microglia. In vivo experiments confirmed that the HHQK peptide reduces rat brain inflammation elicited after infusion of Aβ peptides or implantation of native plaque fragments. Strategies which exploit HHQK-like agents may offer a specific therapy to block plaque-induced microgliosis and, in this way, slow the neuronal loss and dementia of Alzheimer's disease. Alzheimer's disease 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine low density lipoprotein diethylpyrocarbonate 4-methyl- umbelliferyl-β-d-xyloside. Alzheimer's disease (AD)1 is a neurodegenerative dementia associated with loss of neurons and the appearance of reactive glia (1Armbrustmacher V.W. Pathol. Annu. 1979; 14: 145-173PubMed Google Scholar, 2Terry R.D. Masliah E. Hansen L.A. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: 179-196Google Scholar). The neuropathological hallmarks of this disorder include neuritic and core senile plaques, which are complex aggregations of proteins composed largely of a 42-residue peptide, β-amyloid (Aβ1–42) (3Roher A.E. Palmer K.C. Yurewicz E.C. Ball M.J. Greenberg B.D. J. Neurochem. 1993; 61: 1916-1926Crossref PubMed Scopus (120) Google Scholar). A preponderance of evidence indicates that a chronic imbalance in the production and clearance of Aβ initiates pathological responses, which include neuritic and synaptic abnormalities, neurofibrillary tangles, and loss of neurotransmitters (4Selkoe D.J. Trends Neurosci. 1993; 16: 403-409Abstract Full Text PDF PubMed Scopus (433) Google Scholar). Although Aβ peptides found within senile plaques are widely believed to damage the nervous system (4Selkoe D.J. Trends Neurosci. 1993; 16: 403-409Abstract Full Text PDF PubMed Scopus (433) Google Scholar), the mechanisms by which these molecules actually drive AD pathology remain uncertain. One pathway for Aβ-induced neuron damage may involve inflammatory cells, for it has long been recognized that reactive microglia are closely associated with neuritic and core plaques (5Bolsi D. Riv. Patol. Nerv. Ment. 1927; 32: 65-72Google Scholar, 6Frackowiak J. Wisniewski H.M. Wegiel J. Merz G.S. Iqbal K. Wang K.C. Acta Neuropathol. 1992; 84: 225-233Crossref PubMed Scopus (230) Google Scholar, 7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, 8McGeer P.L. Itagaki S. Boyes B.E. McGeer E.G. Neurology. 1988; 38: 1285-1291Crossref PubMed Google Scholar). Since reactive microglia release such bioactive agents as proteolytic enzymes, cytokines, free radicals, and nitric oxide (9Giulian D. Curr. Top. Neurol. 1992; 12: 23-54Google Scholar, 10Banati R.B. Gehrmann J. Schubert P. Kreutzberg G.W. Glia. 1993; 7: 111-118Crossref PubMed Scopus (934) Google Scholar, 11Lees G.J. J. Neurol. Sci. 1993; 114: 119-122Abstract Full Text PDF PubMed Scopus (185) Google Scholar), the immunopathology of AD is likely to involve microglial release of cellular poisons. Recent studies also show that exposure to neuritic and core plaques stimulated cultured human microglia to secrete a potent neurotoxic amine that was found in the AD brain (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Moreover, Aβ1–42, the most abundant component of neuritic and core plaques (12Roher A.E. Lowenson J.D. Clarke S. Wolkow C. Wang R. Cotter R.J. Reardon I.M. Zurcher-Neely H.A. Heinrikson R.L. Ball M.J. Greenberg B.D. J. Biol. Chem. 1993; 268: 3072-3083Abstract Full Text PDF PubMed Google Scholar) served as the major plaque-derived signal to evoke neuron-killing by microglia (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). As described here, Aβ13–16 (HHQK) is necessary for an initial microglial interaction with plaque through a cell-surface binding site involving heparan sulfate. Small peptides containing HHQK block plaque induction of neurotoxic microglia in vitro and reduce inflammation in vivo. Strategies exploiting HHQK-like agents to suppress plaque-microglia interactions offer a selective means to prevent AD immunopathology.DISCUSSIONGliosis is an important feature of AD pathology and is closely associated with senile plaques and neuronal injury. Histological study shows, for example, that nearly all neuritic and core plaques are surrounded by clusters of reactive microglia (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, 29Perlmutter L.S. Barron E. Chui H.C. Neurosci. Lett. 1990; 119: 32-36Crossref PubMed Scopus (198) Google Scholar). In vitro studies confirm that quiescent microglia found in normal brain will become reactive when placed in contact with isolated neuritic/core plaque fragments, as demonstrated by changes in morphology and release of neurotoxins (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Such cell culture observations support the idea that immune responses contribute to the neuronal pathology of AD. Further study has shown that plaque-activated microglia produce a neurotoxic amine which can also be recovered from brain tissues heavily laden with clusters of reactive microglia (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Moreover, this toxin was found to destroy hippocampal pyramidal cells. Since the hippocampus participates in memory and cognition (2Terry R.D. Masliah E. Hansen L.A. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: 179-196Google Scholar), it is reasonable to implicate microglia-derived toxins as destroyers of cognitive function in AD patients (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar).To of AD plaque of cultured microglia. studies of native neuritic and core plaques shown that Aβ and such as or were the which microglial (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). that human Aβ1–42 and were the most for neurotoxic microglia was (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). As described here, modifications of peptides the of human Aβ by that Aβ13–16 HHQK was necessary for induction of neurotoxic microglia observations to study the binding of Aβ peptides to microglia. Such experiments were by the of Aβ1–42 to and as it was with cell culture In to a for Aβ1–42 to to plaques for binding Such elicited as native of small Aβ peptides containing the HHQK domain microglial binding to Aβ1–42 and induction of microglial Moreover, of microglia that proteins were in this binding Further showed Aβ induction of neurotoxicity heparan sulfate to and associated with microglial for an HHQK binding Since residues of Aβ as a binding domain for heparan sulfate S. D. P. Greenberg R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Neurochem. 1993; 61: PubMed Scopus (120) Google Scholar, R. D. P. K. 12: Full Text PDF PubMed Scopus Google Scholar), that membrane-associated heparan sulfate an important in the immunopathology of AD by plaque to brain inflammatory that the major of neuritic and core plaques, participates in the neuron that the dementia of AD. Aβ peptides as cell M.J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), these peptides as of a complex P. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: Scholar). vitro support example, a peptide, will damage a of cells, and when in (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar, C. J.B. R. Schubert D. 7: Full Text PDF Scopus Google Scholar, R. E. PubMed Scopus Google Scholar). This of is from the neuron-killing mediated by Aβ of brain inflammatory described the the of the of is and of glia (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). studies show the of the neuronal in microglia-derived (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar), free production necessary for the D. C. R. Sci. S. 1995; PubMed Scopus Google Scholar). Aβ1–42 will neurotoxic microglia or (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). the microglia-derived is selective to a of cell Since the of disease will be by of AD it be that has been found to as a in AD brain or in cultured K. D.J. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, J. K. Iqbal K. 1993; PubMed Scopus Google Scholar, R. D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google been to neuronal damage by microglia and AD (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, D. J. J. J. Neurosci. PubMed Google D. C. Neurol. 1990; 27: PubMed Scopus Google Scholar, P.L. McGeer E. J. J. 1990; PubMed Scopus Google Scholar, Biol. Full Text PDF PubMed Scopus Google Scholar). that neuron as by the culture system here, has to cellular in AD a of neuron selective by neuritic/core plaques and a high to human Aβ peptides Importantly, this to in the immunopathology of AD and to immune to the of the for a to suppress microgliosis in AD. Small peptides with the HHQK domain with plaques for binding to microglia and in this block plaque induction of neuron-killing Importantly, HHQK of neuron-killing has for Aβ and prevent microglial by such as and Such a selective of plaque-microglia interactions is for it responses to immune that the HHQK domain of β-amyloid plaques block pathology to Alzheimer's disease. Alzheimer's disease (AD)1 is a neurodegenerative dementia associated with loss of neurons and the appearance of reactive glia (1Armbrustmacher V.W. Pathol. Annu. 1979; 14: 145-173PubMed Google Scholar, 2Terry R.D. Masliah E. Hansen L.A. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: 179-196Google Scholar). The neuropathological hallmarks of this disorder include neuritic and core senile plaques, which are complex aggregations of proteins composed largely of a 42-residue peptide, β-amyloid (Aβ1–42) (3Roher A.E. Palmer K.C. Yurewicz E.C. Ball M.J. Greenberg B.D. J. Neurochem. 1993; 61: 1916-1926Crossref PubMed Scopus (120) Google Scholar). A preponderance of evidence indicates that a chronic imbalance in the production and clearance of Aβ initiates pathological responses, which include neuritic and synaptic abnormalities, neurofibrillary tangles, and loss of neurotransmitters (4Selkoe D.J. Trends Neurosci. 1993; 16: 403-409Abstract Full Text PDF PubMed Scopus (433) Google Scholar). Although Aβ peptides found within senile plaques are widely believed to damage the nervous system (4Selkoe D.J. Trends Neurosci. 1993; 16: 403-409Abstract Full Text PDF PubMed Scopus (433) Google Scholar), the mechanisms by which these molecules actually drive AD pathology remain uncertain. One pathway for Aβ-induced neuron damage may involve inflammatory cells, for it has long been recognized that reactive microglia are closely associated with neuritic and core plaques (5Bolsi D. Riv. Patol. Nerv. Ment. 1927; 32: 65-72Google Scholar, 6Frackowiak J. Wisniewski H.M. Wegiel J. Merz G.S. Iqbal K. Wang K.C. Acta Neuropathol. 1992; 84: 225-233Crossref PubMed Scopus (230) Google Scholar, 7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, 8McGeer P.L. Itagaki S. Boyes B.E. McGeer E.G. Neurology. 1988; 38: 1285-1291Crossref PubMed Google Scholar). Since reactive microglia release such bioactive agents as proteolytic enzymes, cytokines, free radicals, and nitric oxide (9Giulian D. Curr. Top. Neurol. 1992; 12: 23-54Google Scholar, 10Banati R.B. Gehrmann J. Schubert P. Kreutzberg G.W. Glia. 1993; 7: 111-118Crossref PubMed Scopus (934) Google Scholar, 11Lees G.J. J. Neurol. Sci. 1993; 114: 119-122Abstract Full Text PDF PubMed Scopus (185) Google Scholar), the immunopathology of AD is likely to involve microglial release of cellular poisons. Recent studies also show that exposure to neuritic and core plaques stimulated cultured human microglia to secrete a potent neurotoxic amine that was found in the AD brain (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Moreover, Aβ1–42, the most abundant component of neuritic and core plaques (12Roher A.E. Lowenson J.D. Clarke S. Wolkow C. Wang R. Cotter R.J. Reardon I.M. Zurcher-Neely H.A. Heinrikson R.L. Ball M.J. Greenberg B.D. J. Biol. Chem. 1993; 268: 3072-3083Abstract Full Text PDF PubMed Google Scholar) served as the major plaque-derived signal to evoke neuron-killing by microglia (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). As described here, Aβ13–16 (HHQK) is necessary for an initial microglial interaction with plaque through a cell-surface binding site involving heparan sulfate. Small peptides containing HHQK block plaque induction of neurotoxic microglia in vitro and reduce inflammation in vivo. Strategies exploiting HHQK-like agents to suppress plaque-microglia interactions offer a selective means to prevent AD is an important feature of AD pathology and is closely associated with senile plaques and neuronal injury. Histological study shows, for example, that nearly all neuritic and core plaques are surrounded by clusters of reactive microglia (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, 29Perlmutter L.S. Barron E. Chui H.C. Neurosci. Lett. 1990; 119: 32-36Crossref PubMed Scopus (198) Google Scholar). In vitro studies confirm that quiescent microglia found in normal brain will become reactive when placed in contact with isolated neuritic/core plaque fragments, as demonstrated by changes in morphology and release of neurotoxins (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Such cell culture observations support the idea that immune responses contribute to the neuronal pathology of AD. Further study has shown that plaque-activated microglia produce a neurotoxic amine which can also be recovered from brain tissues heavily laden with clusters of reactive microglia (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Moreover, this toxin was found to destroy hippocampal pyramidal cells. Since the hippocampus participates in memory and cognition (2Terry R.D. Masliah E. Hansen L.A. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: 179-196Google Scholar), it is reasonable to implicate microglia-derived toxins as destroyers of cognitive function in AD patients (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar).To of AD plaque of cultured microglia. studies of native neuritic and core plaques shown that Aβ and such as or were the which microglial (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). that human Aβ1–42 and were the most for neurotoxic microglia was (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). As described here, modifications of peptides the of human Aβ by that Aβ13–16 HHQK was necessary for induction of neurotoxic microglia observations to study the binding of Aβ peptides to microglia. Such experiments were by the of Aβ1–42 to and as it was with cell culture In to a for Aβ1–42 to to plaques for binding Such elicited as native of small Aβ peptides containing the HHQK domain microglial binding to Aβ1–42 and induction of microglial Moreover, of microglia that proteins were in this binding Further showed Aβ induction of neurotoxicity heparan sulfate to and associated with microglial for an HHQK binding Since residues of Aβ as a binding domain for heparan sulfate S. D. P. Greenberg R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Neurochem. 1993; 61: PubMed Scopus (120) Google Scholar, R. D. P. K. 12: Full Text PDF PubMed Scopus Google Scholar), that membrane-associated heparan sulfate an important in the immunopathology of AD by plaque to brain inflammatory that the major of neuritic and core plaques, participates in the neuron that the dementia of AD. Aβ peptides as cell M.J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), these peptides as of a complex P. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: Scholar). vitro support example, a peptide, will damage a of cells, and when in (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar, C. J.B. R. Schubert D. 7: Full Text PDF Scopus Google Scholar, R. E. PubMed Scopus Google Scholar). This of is from the neuron-killing mediated by Aβ of brain inflammatory described the the of the of is and of glia (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). studies show the of the neuronal in microglia-derived (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar), free production necessary for the D. C. R. Sci. S. 1995; PubMed Scopus Google Scholar). Aβ1–42 will neurotoxic microglia or (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). the microglia-derived is selective to a of cell Since the of disease will be by of AD it be that has been found to as a in AD brain or in cultured K. D.J. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, J. K. Iqbal K. 1993; PubMed Scopus Google Scholar, R. D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google been to neuronal damage by microglia and AD (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, D. J. J. J. Neurosci. PubMed Google D. C. Neurol. 1990; 27: PubMed Scopus Google Scholar, P.L. McGeer E. J. J. 1990; PubMed Scopus Google Scholar, Biol. Full Text PDF PubMed Scopus Google Scholar). that neuron as by the culture system here, has to cellular in AD a of neuron selective by neuritic/core plaques and a high to human Aβ peptides Importantly, this to in the immunopathology of AD and to immune to the of the for a to suppress microgliosis in AD. Small peptides with the HHQK domain with plaques for binding to microglia and in this block plaque induction of neuron-killing Importantly, HHQK of neuron-killing has for Aβ and prevent microglial by such as and Such a selective of plaque-microglia interactions is for it responses to immune that the HHQK domain of β-amyloid plaques block pathology to Alzheimer's disease. is an important feature of AD pathology and is closely associated with senile plaques and neuronal injury. Histological study shows, for example, that nearly all neuritic and core plaques are surrounded by clusters of reactive microglia (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, 29Perlmutter L.S. Barron E. Chui H.C. Neurosci. Lett. 1990; 119: 32-36Crossref PubMed Scopus (198) Google Scholar). In vitro studies confirm that quiescent microglia found in normal brain will become reactive when placed in contact with isolated neuritic/core plaque fragments, as demonstrated by changes in morphology and release of neurotoxins (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Such cell culture observations support the idea that immune responses contribute to the neuronal pathology of AD. Further study has shown that plaque-activated microglia produce a neurotoxic amine which can also be recovered from brain tissues heavily laden with clusters of reactive microglia (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar). Moreover, this toxin was found to destroy hippocampal pyramidal cells. Since the hippocampus participates in memory and cognition (2Terry R.D. Masliah E. Hansen L.A. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: 179-196Google Scholar), it is reasonable to implicate microglia-derived toxins as destroyers of cognitive function in AD patients (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). of AD plaque of cultured microglia. studies of native neuritic and core plaques shown that Aβ and such as or were the which microglial (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). that human Aβ1–42 and were the most for neurotoxic microglia was (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). As described here, modifications of peptides the of human Aβ by that Aβ13–16 HHQK was necessary for induction of neurotoxic microglia observations to study the binding of Aβ peptides to microglia. Such experiments were by the of Aβ1–42 to and as it was with cell culture In to a for Aβ1–42 to to plaques for binding Such elicited as native of small Aβ peptides containing the HHQK domain microglial binding to Aβ1–42 and induction of microglial Moreover, of microglia that proteins were in this binding Further showed Aβ induction of neurotoxicity heparan sulfate to and associated with microglial for an HHQK binding Since residues of Aβ as a binding domain for heparan sulfate S. D. P. Greenberg R. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J. Neurochem. 1993; 61: PubMed Scopus (120) Google Scholar, R. D. P. K. 12: Full Text PDF PubMed Scopus Google Scholar), that membrane-associated heparan sulfate an important in the immunopathology of AD by plaque to brain inflammatory cells. that the major of neuritic and core plaques, participates in the neuron that the dementia of AD. Aβ peptides as cell M.J. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), these peptides as of a complex P. Terry R.D. Katzman R. Bick K.L. Alzheimer Disease. Raven Press, New York1994: Scholar). vitro support example, a peptide, will damage a of cells, and when in (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar, C. J.B. R. Schubert D. 7: Full Text PDF Scopus Google Scholar, R. E. PubMed Scopus Google Scholar). This of is from the neuron-killing mediated by Aβ of brain inflammatory described the the of the of is and of glia (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). studies show the of the neuronal in microglia-derived (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar), free production necessary for the D. C. R. Sci. S. 1995; PubMed Scopus Google Scholar). Aβ1–42 will neurotoxic microglia or (13Giulian D. Haverkamp L.J., Yu, J.H. Karshin W. Tom D. Li J. Kirkpatrick J Kuo Y.M. Roher A.E. J. Neurosci. 1996; 16: 6021-6037Crossref PubMed Google Scholar). the microglia-derived is selective to a of cell Since the of disease will be by of AD it be that has been found to as a in AD brain or in cultured K. D.J. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, J. K. Iqbal K. 1993; PubMed Scopus Google Scholar, R. D. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). been to neuronal damage by microglia and AD (7Giulian D. Haverkamp L.J. Li J. Karshin W.L., Yu, J. Tom D. Li X. Kirkpatrick J.B. Neurochem. Int. 1995; 27: 119-137Crossref PubMed Scopus (206) Google Scholar, D. J. J. J. Neurosci. PubMed Google D. C. Neurol. 1990; 27: PubMed Scopus Google Scholar, P.L. McGeer E. J. J. 1990; PubMed Scopus Google Scholar, Biol. Full Text PDF PubMed Scopus Google Scholar). that neuron as by the culture system here, has to cellular in AD a of neuron selective by neuritic/core plaques and a high to human Aβ peptides Importantly, this to in the immunopathology of AD and to immune to the of the for a to suppress microgliosis in AD. Small peptides with the HHQK domain with plaques for binding to microglia and in this block plaque induction of neuron-killing Importantly, HHQK of neuron-killing has for Aβ and prevent microglial by such as and Such a selective of plaque-microglia interactions is for it responses to immune that the HHQK domain of β-amyloid plaques block pathology to Alzheimer's disease. of for of peptides and of of for
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Hydrogen peroxide mediates amyloid β protein toxicity
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