Abstract: The present invention is disubstituted amines of formula (I) and disubstituted amines of formula (II) useful in treating Alzheimer's disease and other similar diseases.

Abstract: The invention provides assays and methods for determining whether a compound inhibits gamma secretase in a substrate specific manner. The invention provides an isolated cell wherein the cell stably expresses APP and at least one gamma secretase substrate other than APP. The invention provides assays and methods comprising contacting a cell with gamma secretase and detecting production of Abeta, detecting production of intracellular domain (ICD), and detecting a signal from a reporter gene under transcriptional control of the ICD. The invention also provides compounds that inhibit gamma secretase, pharmaceutical compositions comprising such compounds, and methods of treating Alzheimer's disease using such compounds.

Abstract: Disclosed are compounds of the formula: where variables Q, Z, X, R15, R2, R3, and Rc are defined herein. Compounds disclosed herein are inhibitors of the beta-secretase enzyme and are therefore useful in the treatment of Alzheimer's disease and other diseases characterized by deposition of A beta peptide in a mammal.

Abstract: Disclosed are various forms of an active, isolated ?-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the brains of individuals afflicted with Alzheimer's disease. Recombinant cells that produce this enzyme either alone or in combination with some of its natural substrates (?-APPwt and ?-APPsw) are also disclosed, as are antibodies directed to such proteins. These compositions are useful for use in methods of selecting compounds that modulate ?-secretase. Inhibitors of ?-secretase are implicated as therapeutics in the treatment of neurodegenerative diseases, such as Alzheimer's disease.

Abstract: Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Abstract: The present invention provides a crystal of human beta-secretase (BACE) having monoclinic space group symmetry C2, in a representative example, comprising a unit cell having dimensions of a, b, and c, wherein a is about 53 ? to about 103 ?, b is about 85 ? to about 125 ?, c is about 40 ? to about 60 ?, and ?=?=90°, and ? is about 85° to about 105°, and in a preferred example, comprising unit cell dimensions as follows: a is 73.1 ?, b is 105.1 ?, c is 50.5 ?, and ?=?=90°, and ? is 94.8, wherein the Matthews coefficient of said crystal is 2.1 ?/Da with 42% solvent, and wherein said crystal diffracts to 1.7 ? resolution.

Abstract: The present invention is direct to a method of producing analgesia in a mammalian subject. The method includes administering to the subject an omega conopeptide, preferably ziconotide, in combination with an analgesic selected from the group consisting of morphine, bupivacaine, clonidine, hydromorphone, baclofen, fentanyil, buprenorphine, and sufentanil, or its pharmaceutically acceptable salts thereof, wherein the ?-conopeptide retains its potency and is physically and chemically compatible with the analgesic compound. A preferred route of administration is intrathecal administration, particularly continuous intrathecal infusion. The present invention is also directed to a pharmaceutical formulation comprising an omega conopeptide, preferably ziconotide, an antioxidant, in combination with an analgesic selected from the group consisting of morphine, bupivacaine, clonidine, hydromorphone, baclofen, fentanyl, buprenorphine, and sufentanil.

Abstract: The present invention features methods and compositions for inhibiting amyloidogenic protein toxicity, inhibiting formation of an amyloidogenic protein deposit and/or treating amyloidogenic diseases by administering a pharmaceutically effective amount of one or more agents that bind an integrin or an integrin subunit.

Abstract: Disclosed is an active, isolated ?-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the brains of individuals afflicted with Alzheimer's disease. Recombinant cells that produce this enzyme either alone or in combination with some of its natural substrates (APP and APPsw) are also disclosed. These compositions are useful for use in methods of selecting compounds that modulate ?-secretase. Inhibitors of ?-secretase are implicated as therapeutics in the treatment of neurodegenerative diseases, such as Alzheimer's disease.

Abstract: Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a human or animal subject such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Abstract: This present invention relates to prodrug compounds of the formula (Y) and pharmaceutical salts thereof: where RN, R1, R2, R3R4 and RC are defined herein, which are useful in treating Alzheimer's disease and other similar diseases.

Abstract: The application identifies novel fragments of alpha-synuclein in patients with Lewy Body Disease (LBD) and transgenic animal models thereof. These diseases are characterized by aggregations of alpha-synuclein. The fragments have a truncated C-terminus relative to full-length alpha-synuclein. Some fragments are characterized by a molecular weight of about 12 kDa as determined by SDS gel electrophoresis in tricine buffer and a truncation of at least ten contiguous amino acids from the C-terminus of natural alpha-synuclein. The site of cleavage preferably occurs after residue 117 and before residue 126 of natural alpha-synuclein. The identification of these novel fragments of alpha-synuclein has a number of application in for example, drug discovery, diagnostics, therapeutics, and transgenic animals.

Abstract: Human BACE polypeptides having modifications to the N-linked glycosylation sites including one or more of the following amino acid substitutions: S174I, N223A, N153Q and N354S. DNA sequences, vectors, and host cells for producing the polypeptides. Crystalline protein compositions formed from the purified polypeptides. Methods of screening for compounds that inhibit A? using the polypeptides.

Abstract: The invention provides in vitro, ex vivo, and in vivo assays for Parkin activity, in which Parkin-mediated ubiquitination of a Sept4 protein is measured. The assays may be used to screen for agents that modulate Parkin protein ligase activity.

Abstract: The invention provides assays and methods for determining the substrate specificity of gamma secretase inhibitors and for identifying substrate-selective (and substrate isoform-selective) inhibitors of gamma secretase. The invention provides assays and methods for determining whether a compound inhibits gamma secretase in a site specific or substrate specific manner. The invention provides isolated polypeptide sequences comprising modified gamma secretase substrates, and polynucleotide sequences encoding the polypeptide sequences. The invention also provides compounds that inhibit gamma secretase, pharmaceutical compositions comprising such compounds, and methods of treating Alzheimer's disease using such compounds.

Abstract: The present invention is directed to methods of producing conjugates of A? peptide immunogens with protein/polypeptide carrier molecules, which are useful as immunogens, wherein peptide immunogens are conjugated to protein carriers via activated functional groups on amino acid residues of the carrier or of the optionally attached linker molecule, and wherein any unconjugated reactive functional groups on amino acid residues are inactivated via capping, thus retaining the immunological functionality of the carrier molecule, but reducing the propensity for undesirable reactions that could render the conjugate less safe or effective. Furthermore, the invention also relates to such immunogenic products and immunogenic compositions containing such immunogenic products made by such methods.

Abstract: The invention provides agents and methods for treatment of diseases associated with Lewy body diseases (LBDs) in the brain of a patient. Preferred agents include inhibitors of PLK2 kinase.

Abstract: Disclosed are methods for treating Alzheimer's disease, and other diseases, and/or inhibiting beta-secretase enzyme, and/or inhibiting deposition of A beta peptide in a mammal, by use of compounds of formula (I) wherein X, R1, and R2 are defined herein.

Abstract: The invention provides in vitro and cell-based assays for parkin activity, in which parkin-mediated ubiquitination of the S5a subunit of the 26S proteasome is measured, or ubiquitination of troponin 1. The assays may be used to screen for agents that modulate parkin protein ligase activity.

Abstract: Disclosed is an active, isolated ?-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the brains of individuals afflicted with Alzheimer's disease. Recombinant cells that produce this enzyme either alone or in combination with some of its natural substrates (APP and APPsw) are also disclosed. These compositions are useful for use in methods of selecting compounds that modulate ?-secretase. Inhibitors of ?-secretase are implicated as therapeutics in the treatment of neurodegenerative diseases, such as Alzheimer's disease.