Abstract: We have discovered that LRG-47 (also called p47 GTPase), plays a central role in the pathogenesis of multiple sclerosis, and that inhibition of LRG-47 activity by anti-LRG-47 antibodies or of LRG-47 expression by siRNA dramatically reduce the pathology and symptoms of multiple sclerosis. Certain embodiments of the invention are directed to the therapeutic use of anti-LRG-47 antibodies (mouse or rabbit or other antibodies that are humanized or human antibodies to LRG-47, preferably antibodies made against human LRG-47) or siRNA or antisense nucleotides that specifically hybridize with the gene or mRNA or cDNA encoding human LRG-47 to treat or prevent multiple sclerosis and other autoimmune diseases that are T-cell-mediated. Other embodiments are directed to methods for the diagnosis of multiple sclerosis or to determining the aggressiveness of multiple sclerosis by determining the amount of human LRG-47 or LRG-47 mRNA in a biological sample from the patient.

Abstract: We have discovered that LRG-47 (also called p47 GTPase), plays a central role in the pathogenesis of multiple sclerosis, and that inhibition of LRG-47 activity by anti-LRG-47 antibodies or of LRG-47 expression by siRNA dramatically reduce the pathology and symptoms of multiple sclerosis. Certain embodiments of the invention are directed to the therapeutic use of anti-LRG-47 antibodies (mouse or rabbit or other antibodies that are humanized or human antibodies to LRG-47, preferably antibodies made against human LRG-47) or siRNA or antisense nucleotides that specifically hybridize with the gene or mRNA or cDNA encoding human LRG-47 to treat or prevent multiple sclerosis and other autoimmune diseases that are T-cell-mediated. Other embodiments are directed to methods for the diagnosis of multiple sclerosis or to determining the aggressiveness of multiple sclerosis by determining the amount of human LRG-47 or LRG-47 mRNA in a biological sample from the patient.

Abstract: This invention provides methods, compositions and articles of manufacture for inhibiting binding between A? protein and ABAD in cells. Uses of this invention include, for example, treating Alzheimer's disease; reducing free radical generation, DNA fragmentation, and cytochrome C release in cells; and preserving cell viability by preventing LDH release from a cell.

Abstract: The present invention provides for a transgenic non-human animal whose cells contain a DNA sequence comprising: (a) a nerve tissue specific promoter; and (b) a DNA sequence which encodes a receptor for advanced glycation endproducts (RAGE), wherein the promoter and the DNA sequence which encodes the receptor for advanced glycation endproducts (RAGE) are operatively linked to each other and integrated in the genome of the non-human animal, and wherein said non-human animal exhibits a reduced amount of cerebral tissue infarcted following a transient middle cerebral artery occlusion compared to an identical non-human animal lacking said DNA sequence.

Abstract: The present invention provides for a transgenic non-human animal whose cells contain a DNA sequence comprising: (a) a nerve tissue specific promoter; and (b) a DNA sequence which encodes a receptor for advanced glycation endproducts (RAGE), wherein the promoter and the DNA sequence which encodes the receptor for advanced glycation endproducts (RAGE) are operatively linked to each other and integrated in the genome of the non-human animal, and wherein said non-human animal exhibits a reduced amount of cerebral tissue infarcted following a transient middle cerebral artery occlusion compared to an identical non-human animal lacking said DNA sequence.

Abstract: This invention provides methods, compositions and articles of manufacture for inhibiting binding between A? protein and ABAD in cells. Uses of this invention include, for example, treating Alzheimer's disease; reducing free radical generation, DNA fragmentation, and cytochrome C release in cells; and preserving cell viability by preventing LDH release from a cell.

Abstract: The present invention provides for a transgenic non-human animal whose cells contain a DNA sequence comprising: (a) a nerve tissue specific promoter; and (b) a DNA sequence which encodes a receptor for advanced glycation endproducts (RAGE), wherein the promoter and the DNA sequence which encodes the receptor for advanced glycation endproducts (RAGE) are operatively linked to each other and integrated in the genome of the non-human animal, and wherein said non-human animal exhibits a reduced amount of cerebral tissue infarcted following a transient middle cerebral artery occlusion compared to an identical non-human animal lacking said DNA sequence.

Abstract: The present invention provides for a transgenic non-human animal whose cells contain a DNA sequence comprising: (a) a nerve tissue specific promoter; and (b) a DNA sequence which encodes a receptor for advanced glycation endproducts (RAGE), wherein the promoter and the DNA sequence which encodes the receptor for advanced glycation endproducts (RAGE) are operatively linked to each other and integrated in the genome of the non-human animal, and wherein said non-human animal exhibits a reduced amount of cerebral tissue infarcted following a transient middle cerebral artery occlusion compared to an identical non-human animal lacking said DNA sequence.

Abstract: The present invention is directed to methods for treating or preventing Alzheimer's disease by administering therapeutically effective amounts of an agent that reduces Cyclophilin D expression in a patient, or that reduce Cyclophilin D activity or its ability to form a complex with Amyloid beta. Such agents include antisense nucleotides and small interfering RNAs, antibodies that selectively bind to Cyclophilin D, and cyclosporine A and D.

Abstract: We have discovered that LRG-47 (also called p47 GTPase), plays a central role in the pathogenesis of multiple sclerosis, and that inhibition of LRG-47 activity by anti-LRG-47 antibodies or of LRG-47 expression by siRNA dramatically reduce the pathology and symptoms of multiple sclerosis. Certain embodiments of the invention are directed to the therapeutic use of anti-LRG-47 antibodies (mouse or rabbit or other antibodies that are humanized or human antibodies to LRG-47, preferably antibodies made against human LRG-47) or siRNA or antisense nucleotides that specifically hybridize with the gene or mRNA or cDNA encoding human LRG-47 to treat or prevent multiple sclerosis and other autoimmune diseases that are T-cell-mediated. Other embodiments are directed to methods for the diagnosis of multiple sclerosis or to determining the aggressiveness of multiple sclerosis by determining the amount of human LRG-47 or LRG-47 mRNA in a biological sample from the patient.

Abstract: Disclosed are RAGE fusion proteins comprising RAGE polypeptide sequences linked to a second, non-RAGE polypeptide. The RAGE fusion protein may utilize a RAGE polypeptide domain comprising a RAGE ligand binding site and an interdomain linker directly linked to an immunoglobulin CH2 domain. Such fusion proteins may provide specific, high affinity binding to RAGE ligands. Also disclosed is the use of the RAGE fusion proteins as therapeutics for RAGE-mediated pathologies.

Abstract: This invention provides a method of inhibiting the binding of beta-sheet fibril to RAGE on the surface of a cell which comprises contacting the cell with a binding-inhibiting amount of a compound capable of inhibiting binding of beta-sheet fibril to RAGE so as to thereby inhibit binding of beta-sheet fibril to RAGE. In one embodiment, the beta-sheet fibril is amyloid fibril. In one embodiment, the compound is sRAGE or a fragment thereof. In another embodiment, the compound is an anti-RAGE antibody or portion thereof. This invention provides the above method wherein the inhibition of binding of the beta-sheet fibril to RAGE has the consequences of decreasing the load of beta-sheet fibril in the tissue, inhibiting fibril-induced programmed cell death, and inhibiting fibril-induced cell stress. This invention also provides methods of determining whether a compound inhibits binding of a beta-sheet fibril to RAGE on the surface of a cell.

Abstract: This invention provides methods, compositions and articles of manufacture for inhibiting binding between A? protein and ABAD in cells. Uses of this invention include, for example, treating Alzheimer's disease; reducing free radical generation, DNA fragmentation, and cytochrome C release in cells; and preserving cell viability by preventing LDH release from a cell.

Abstract: This invention provides a method for treating a subject either during or soon after a seizure, in order to reduce the extent of neuronal damage in the subject resulting from the seizure comprising administering to the subject, either during or soon after the seizure, a therapeutically effective amount of an inhibitor of receptor for advanced glycation endproducts (RAGE), so as to thereby reduce the extent of neuronal damage in the subject. This invention further provides a method for inhibiting neuronal damage which would otherwise result from a seizure in a subject predisposed to having a seizure, comprising administering to the subject a prophylactically effective amount of an inhibitor of receptor for advanced glycation endproducts (RAGE), so as to inhibit neuronal damage which would otherwise result from a seizure in the event the subject were to suffer a seizure.

Abstract: The present invention provides a method for treating inflammation in a subject which comprises administering to the subject soluble receptor for advanced glycation endproduct (sRAGE) in an amount effective to inhibit binding of advanced glycation endproducts (AGEs) to RAGE thereby treating inflammation in the subject. The present invention also provides for a method for treating inflammation in a subject which comprises administering to the subject an agent in an amount effective to inhibit the interaction between receptor for advanced glycation endproduct (RAGE) and its ligand thereby treating inflammation in the subject.

Abstract: The present invention provides a method for treating inflammation in a subject which comprises administering to the subject soluble receptor for advanced glycation endproduct (sRAGE) in an amount effective to inhibit binding of advanced glycation endproducts (AGEs) to RAGE thereby treating inflammation in the subject. The present invention also provides for a method for treating inflammation in a subject which comprises administering to the subject an agent in an amount effective to inhibit the interaction between receptor for advanced glycation endproduct (RAGE) and its ligand thereby treating inflammation in the subject.

Abstract: The present invention provides for a transgenic non-human animal whose cells contain a DNA sequence comprising: (a) a nerve tissue specific promoter operatively linked to a DNA sequence which encodes amyloid-beta peptide alcohol dehydrogenase (ABAD), and (b) a nerve tissue specific promoter operatively linked to a DNA sequence encoding a mutant human amyloid precursor protein hAPP695, hAPP751 and hAPP770 bearing mutations linked to familial Alzheimer's disease in humans, wherein the non-human animal exhibits at least one phenotype from the group consisting of: reduced basal synaptic transmission; inhibited synaptic plasticity; increased neuronal stress; elevated 4-hydroxynonenal in cerebral cortex; increased heme oxygenase type I in cerebral cortex; decreased synaptophysin in cerebral cortex; decreased micortubule-associated protein 2 in cerebral cortex; and increased levels of activated caspase 3 antigen in cortical neurons.

Abstract: The present invention provides an isolated nucleic acid encoding an endoplasmic reticulum associated amyloid-beta peptide binding (ERAB) polypeptide. The ERAB polypeptide may comprise human ERAB polypeptide. The present invention provides a purified ERAB polypeptide, as well as a method for treating a neurodegenerative condition in a subject which comprises administering to the subject an agent in amount effective to inhibit ERAB polypeptide binding to amyloid-beta peptide so as to thereby treat the neurodegenerative condition.

Abstract: The present invention provides for a transgenic non-human animal whose cells contain a recombinant DNA sequence comprising a nerve tissue specific promoter operatively linked to a DNA sequence which encodes amyloid-beta peptide alcohol dehydrogenase (ABAD), and exhibits at least one phenotype from the group consisting of: overexpression of ABAD, elevated levels of basal ATP; protection from metabolic or ischemic stress.

Abstract: The present invention provides a method for decreasing cerebral vasoconstriction in a subject suffering from chronic or acute cerebral amyloid angiopathy which comprises administering to the subject an inhibitor of receptor for advanced glycation endproduct (RAGE) in an effective amount to inhibit transcytosis of amyloid &bgr; peptides across the blood-brain barrier in the subject, thereby decreasing cerebral vasoconstriction in the subject. The invention further provides for a method for ameliorating neurovascular stress in a subject which comprises administering to the subject an effective amount of an inhibitor of receptor for advanced glycation endproduct (RAGE), so as to increase cerebral blood flow in the subject, thereby ameliorating neurovascular stress in the subject.