PCK ACTIVATION AS A MEANS FOR ENHANCING sAPPa SECRETION AND IMPROVING COGNITION USING BRYOSTATIN TYPE COMPOUNDS
This invention provides a method for isolating and identifying proteins participating in protein-protein interactions in a complex mixture. The method uses a chemically reactive supporting matrix to isolate proteins that in turn non-covalently bind other proteins. The supporting matrix is isolated, and the non-covalently bound proteins are subsequently released for analysis. Because the proteins are accessible to chemical manipulation at both the binding and release steps, identification of the non-covalently bound proteins yields information on specific classes of interacting proteins, such as calcium-dependent or substrate-dependent protein interactions. This permits selection of a subpopulation of proteins from a complex mixture on the basis of specified interaction criteria. The method has the advantage of screening the entire proteome simultaneously, unlike two-hybrid systems or phage display methods which can only detect proteins binding to a single bait protein at a time. The method is applicable to the study of protein-protein interactions in biopsy and autopsy specimens, to the study of protein-protein interactions in the presence of signaling molecules, pharmacological agents or toxins, and for comparison of diseased and normal tissues or cancerous and untransformed cells.
1 - 36 . (canceled)
37 . A method comprising the step of administering a macrocyclic lactone, a benzolactam, a pyrrolidinone or a combination thereof to a subject in need thereof in an amount effective to decrease soluble Aβ-40.
38 . The method of claim 37 , further comprising the step of identifying a subject with increased soluble Aβ-40 levels compared to a control population.
39 . The method of claim 37 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases mean soluble Aβ-40 by about 35%.
40 . The method of claim 37 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases the soluble Aβ-40 by between about 8% and 50%.
41 . The method of claim 38 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases mean soluble Aβ-40 by about 35%.
42 . The method of claim 38 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases the soluble Aβ-40 by between about 8% and 50%.
43 . The method of claim 37 , wherein the macrocyclic lactone is a bryostatin class or neristatin class compound.
44 . The method of claim 43 , wherein the bryostatin class compound is bryostatin-1 through bryostatin-18 or neristatin-1.
45 . The method of claim 38 , wherein the macrocyclic lactone is a bryostatin class or neristatin class compound.
46 . The method of claim 45 , wherein the bryostatin class compound is bryostatin-1 through bryostatin-18 or neristatin-1.
47 . The method of claim 37 , wherein the subject suffers from a neurological disease or disorder.
48 . The method of claim 47 , wherein the neurological disease is Alzheimer's Disease, multi-infarct dementia, the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease, Korsakow's disorder, or attention deficit hyperactivity disorder.
49 . The method of claim 48 , wherein the neurological disease is Alzheimer's Disease.
50 . The method of claim 38 , wherein the subject suffers from a neurological disease or disorder.
51 . The method of claim 50 , wherein the neurological disease is Alzheimer's Disease, multi-infarct dementia, the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease, Korsakow's disorder, or attention deficit hyperactivity disorder.
52 . The method of claim 51 , wherein the neurological disease is Alzheimer's Disease.
53 . A method comprising the step of administering a macrocyclic lactone, a benzolactam, a pyrrolidinone or a combination thereof to a subject in need thereof in an amount effective to decrease soluble Aβ-42.
54 . The method of claim 53 , further comprising the step of identifying a subject with increased soluble Aβ-42 levels compared to a control population.
55 . The method of claim 53 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases mean soluble Aβ-42 by about 59%.
56 . The method of claim 53 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases the soluble Aβ-42 by between about 25% and 77%.
57 . The method of claim 54 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases mean soluble Aβ-42 by about 59%.
58 . The method of claim 54 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof decreases the soluble Aβ-42 by between about 25% and 77%.
59 . The method of claim 53 , wherein the macrocyclic lactone is a bryostatin class or neristatin class compound.
60 . The method of claim 59 , wherein the bryostatin class compound is bryostatin-1 through bryostatin-18 or neristatin-1.
61 . The method of claim 54 , wherein the macrocyclic lactone is a bryostatin class or neristatin class compound.
62 . The method of claim 61 , wherein the bryostatin class compound is bryostatin-1 through bryostatin-18 or neristatin-1.
63 . The method of claim 53 , wherein the subject suffers from a neurological disease or disorder.
64 . The method of claim 63 , wherein the neurological disease is Alzheimer's Disease, multi-infarct dementia, the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease, Korsakow's disorder, or attention deficit hyperactivity disorder.
65 . The method of claim 64 , wherein the neurological disease is Alzheimer's Disease.
66 . The method of claim 54 , wherein the subject suffers from a neurological disease or disorder.
67 . The method of claim 66 , wherein the neurological disease is Alzheimer's Disease, multi-infarct dementia, the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease, Korsakow's disorder, or attention deficit hyperactivity disorder.
68 . The method of claim 67 , wherein the neurological disease is Alzheimer's Disease.
69 . A method comprising the step of administering a macrocyclic lactone, a benzolactam, a pyrrolidinone or a combination thereof in an amount effective to lower total amyloid precursor protein (“APP”).
70 . The method of claim 69 , further comprising the step of identifying a subject with elevated APP levels compared to a control population.
71 . The method of claim 69 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof lowers mean total APP by about 40%.
72 . The method of claim 69 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof lowers the total APP by up to about 67%.
73 . The method of claim 70 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof lowers mean total APP by about 40%.
74 . The method of claim 70 , wherein the macrocyclic lactone, the benzolactam, the pyrrolidinone or the combination thereof lowers the total APP by up to about 67%.
75 . The method of claim 69 , wherein the macrocyclic lactone is a bryostatin class or neristatin class compound.
76 . The method of claim 75 , wherein the bryostatin class compound is bryostatin-1 through bryostatin-18 or neristatin-1.
77 . The method of claim 70 , wherein the macrocyclic lactone is a bryostatin class or neristatin class compound.
78 . The method of claim 77 , wherein the bryostatin class compound is bryostatin-1 through bryostatin-18 or neristatin-1.
79 . The method of claim 69 , wherein the subject suffers from a neurological disease or disorder.
80 . The method of claim 79 , wherein the neurological disease is Alzheimer's Disease, multi-infarct dementia, the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease, Korsakow's disorder, or attention deficit hyperactivity disorder.
81 . The method of claim 80 , wherein the neurological disease is Alzheimer's Disease.
82 . The method of claim 70 , wherein the subject suffers from a neurological disease or disorder.
83 . The method of claim 82 , wherein the neurological disease is Alzheimer's Disease, multi-infarct dementia, the Lewy-body variant of Alzheimer's Disease with or without association with Parkinson's disease; Creutzfeld-Jakob disease, Korsakow's disorder, or attention deficit hyperactivity disorder.
84 . The method of claim 83 , wherein the neurological disease is Alzheimer's Disease.