Materials and methods related to the inflammatory effects of secreted amyloid precursor proteins

Abstract

The present invention provides, inter alia, methods and materials useful to affect the inflammatory/and or neuroprotective effects of secreted amyloid precursor protein. In one broad aspect of the present invention, there are provided methods to reduce inflammation caused by sAPP in the brain of a mammal in need of such reduction, comprising administering a pharmaceutically-effective amount of a compound which inhibits the amino terminal region of sAPP involved in inflammatory response. In particular, a method as described, wherein the amino terminal region inhibited comprises Val 20 to Tyr 303 (using the βPP 695 numbering system) is provided, although a method as above, wherein the amino terminal region inhibited comprises the region which binds ApoE is also provided.

What is claimed is:  
     
         1 . A method to reduce inflammation caused by sAPP in the brain of a mammal inneed of such reduction, comprising administering a pharmaceutically-effective amount of a compound which inhibits the amino terminal region of sAPP involved in inflammatory response.  
     
     
         2 . A method of  claim 1 , wherein the amino terminal region inhibited comprises Val 20  to Tyr 303  using the βAPP 695  numbering system.  
     
     
         3 . A method of  claim 1 , wherein the amino terminal region inhibited comprises the region which binds ApoE.  
     
     
         4 . A method of  claim 1 , wherein the mammal is a human.  
     
     
         5 . A method of  claim 4 , wherein the inflammation is due to reduced levels of ApoE3.  
     
     
         6 . A method of  claim 4 , wherein the inflammation is caused by Alzheimer's disease.  
     
     
         7 . A method of  claim 4 , wherein the inflammation is caused by traumatic brain injury.  
     
     
         8 . A method of  claim 4 , wherein the compound is ApoE3.  
     
     
         9 . A method of  claim 4 , wherein the compound is an mRNA transcript of SEQ ID NO 2.  
     
     
         10 . A method to potentiate the neuroprotective effect of sAPPα in a person in need of such potentiation, comprising administering a pharmaceutically-effective amount of compound which inhibits the amino-terminal region of sAPPα involved in inflammatory response.  
     
     
         11 . A method of  claim 10 , wherein the amino terminal region inhibited comprises Val 20  to Tyr 303  using the βAPP 695  numbering system.  
     
     
         12 . A method of  claim 11 , wherein the amino terminal region inhibited comprises the region which binds ApoE.  
     
     
         13 . A method of  claim 11 , wherein the mammal is a human.  
     
     
         14 . A method of  claim 12 , wherein the inflammation is due to reduced levels of ApoE3.  
     
     
         15 . A method of  claim 12 , wherein the inflammation is caused by Alzheimer's disease.  
     
     
         16 . A method of  claim 12 , wherein the inflammation is caused by traumatic brain injury.  
     
     
         17 . A method of  claim 12 , wherein the compound is ApoE3.  
     
     
         18 . A method of  claim 12 , wherein the compound is an mRNA transcript of SEQ ID NO 2.  
     
     
         19 . An isolated amino acid compound consisting essentially of SEQ ID NO 1.  
     
     
         20 . A method to recombinantly produce an amino acid of SEQ ID NO 1, comprising expressing SEQ ID NO 2.  
     
     
         21 . A method to identify the ability of a test compound to inhibit the inflammatory affects of sAPP, comprising contacting the test compound with sAPP in the presence of cells which are known to produce at least one marker of inflammation, and determining whether at least one marker of inflammation is induced.  
     
     
         22 . A method of  claim 21 , wherein the marker is nitrite production.  
     
     
         23 . A method to identify the ability of a test compound to bind to the region of sAPP responsible for negative inflammatory effects, comprising contacting the test compound with the region of sAPP responsible for negative inflammatory effects and determining whether the test compound binds.  
     
     
         24 . A method of  claim 23 , wherein said region comprises SEQ ID NO 2.  
     
     
         25 . A method of  claim 24 , wherein binding is determined via a coprecipitation assay.