Methods for treatment and prevention of tauopathies and amyloid beta amyloidosis by modulating crf receptor signaling

Abstract

Methods for treating or preventing tauopathies and/or Aβ amyloidosis by modulating CRF receptor signaling. Accumulation of hyperphosphorlyated tau protein in the CNS may be reduced by administration of CRF-R1 selective antagonists and/or CRF-R2 selective agonists. For example, in some aspects, methods for preventing the onset of Alzheimer's disease by administration of CRF-R1 selective antagonist are provided.

1 . A method for delaying the onset or progression of a tauopathy, or blocking and/or delaying the onset of progression of amyloid beta amyloidosis (Aβ amyloidosis), in a subject comprising administering to the subject an effective amount of a CRF-R1 selective antagonist and/or CRF-R2 selective agonist. 
     
     
         2 . The method of  claim 1 , wherein the CRF-R1 selective antagonist has between about 10 and about 100, 1000, or 10,000 fold more antagonist activity of CRF-R1 than CRF-R2. 
     
     
         3 . The method of  claim 1 , wherein the CRF-R1 selective antagonist has essentially no CRF-R2 antagonist activity. 
     
     
         4 . The method of  claim 1 , comprising administering both a CRF-R1 selective antagonist and a CRF-R2 selective agonist. 
     
     
         5 . The method of  claim 4 , wherein the CRF-R2 selective agonist and the CRF-R1 selective antagonist are administered separately and/or in a single formulation. 
     
     
         6 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the CRF-R1 selective antagonist further comprises a central nervous system (CNS) targeting agent. 
     
     
         11 - 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the tauopathy is Alzheimer's disease (AD), Amyotrophic lateral sclerosis/parkinsonism-dementia complex, Argyrophilic grain dementia, Corticobasal degeneration, Creutzfeldt-Jakob disease, Dementia pugilistica, Diffuse neurofibrillary tangles with calcificationa, Down's syndrome, Frontotemporal dementia with parkinsonism (linked to chromosome 17), Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, Myotonic dystrophy, Niemann-Pick disease (type C), Non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, Postencephalitic parkinsonism, Prion protein cerebral amyloid angiopathy, Progressive subcortical gliosis, Progressive supranuclear palsy, Subacute sclerosing panencephalitis or Tangle only dementia. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the tauopathy is further defined as a non-Alzheimer tauopathy. 
     
     
         20 . The method of  claim 1 , further defined as a method for delaying the onset of a tauopathy in a subject. 
     
     
         21 . The method of  claim 20 , wherein the subject is at risk for developing a tauopathy. 
     
     
         22 . The method of  claim 21 , wherein the subject comprises a gene mutation associated with a tauopathy or comprises a family history of tauopathy. 
     
     
         23 . The method of  claim 21 , wherein the subject has reduced cognitive or memory function. 
     
     
         24 . The method of  claim 1 , wherein the subject has been diagnosed with a tauopathy. 
     
     
         25 . The method of  claim 24 , wherein the subject has been diagnosed with AD. 
     
     
         26 . The method of  claim 25 , wherein the subject is human. 
     
     
         27 . (canceled) 
     
     
         28 . The method of  claim 1 , wherein the CRF-R1 selective antagonist is administered topically, intravenously, intradermally, intraarterially, intraperitoneally, intracranially, intrathecally, intracerebroventricularly, mucosally, intraocularally, subcutaneously, or orally. 
     
     
         29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein the CRF-R1 selective antagonist is administered directly to the CNS. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 1 , comprising administering to the subject an effective amount of a CRF-R2 selective agonist. 
     
     
         33 - 47 . (canceled) 
     
     
         48 . The method of  claim 32 , wherein the CRF-R2 selective agonist is administered topically, intravenously, intradermally, intraarterially, intraperitoneally, intracranially, intrathecally, intracerebroventricularly, mucosally, intraocularally, subcutaneously, or orally. 
     
     
         49 - 51 . (canceled) 
     
     
         52 . A method for identifying an agent for treating, preventing the onset or preventing progression of a tauopathy comprising:
 a) administering a candidate agent to an animal;   b) subjecting the animal to a stress;   d) determining tau phosphorylation or insoluble tau accumulation in the CNS following stress wherein a decreased in tau phosphorylation [PP] or decreased insoluble tau accumulation in animals treated with a candidate agent relative to control animals is indicative of activity in treating, preventing the onset or preventing progression of a tauopathy.   
     
     
         53 - 77 . (canceled)