Methods for treating microglial dysfunction

Abstract

Among the various aspects of the present disclosure is the provision of methods of treating a microglial dysfunction-associated diseases, disorder, and conditions. The present disclosure provides for a method for treating microglial dysfunction in a subject having a microglial dysfunction-associated neurodegenerative disease comprising administering to a subject a therapeutically effective amount of a microglial rescuing agent. The present disclosure also provides for a method of reversing neuronal damage in a subject having a microglial dysfunction-associated neurodegenerative disease, wherein the microglial dysfunction-associated neurodegenerative disease is characterized by a single nucleotide polymorphisms (SNPs) or mutation in Trem2 or ApoE affecting microglial functions.

What is claimed is: 
     
         1 . A method for treating a microglial dysfunction-associated neurodegenerative disease in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically effective amount of a composition comprising a microglial rescuing agent, wherein the microglial rescuing agent is one or more of a creatine, a creatine analog, a Dectin-1 agonist or pharmaceutically acceptable salt thereof.   
     
     
         2 . The method of  claim 1 , wherein the microglial dysfunction-associated neurodegenerative disease is Alzheimer's disease. 
     
     
         3 . The method of  claim 1 , wherein the microglial dysfunction-associated neurodegenerative disease is a neurodegenerative disease characterized by SNPs or mutations effecting microglial function, a TREM2 variant, or an ApoE variant, resulting in decreased microglial activity. 
     
     
         4 . The method of  claim 3 , wherein the microglial dysfunction-associated neurodegenerative disease is characterized by single nucleotide polymorphisms (SNPs) or mutation in Trem2 or ApoE affecting microglial activity. 
     
     
         5 . The method of  claim 1 , wherein a therapeutically effective amount of a microglial rescuing agent results in one or more of improved microglial metabolic activity, decreased microglial autophagy, reduced neurite dystrophy, decreased cell death, improved microglia viability or improved microglia numbers. 
     
     
         6 . The method of  claim 2 , wherein the therapeutically effective amount of a microglial rescuing agent results in improved microglia clustering around Aβ plaques or reduced plaque-associated neurite dystrophy. 
     
     
         7 . The method of  claim 1 , wherein the microglial rescuing agent is one or more of creatine, nicotinamide mononucleotide, cyclocreatine, phosphocyclocreatine, Zymosan, and Zymosan Depleted. 
     
     
         8 . The method of  claim 1 , wherein the subject is human. 
     
     
         9 . A method of reversing neuronal damage in a subject having a microglial dysfunction-associated neurodegenerative disease, wherein the microglial dysfunction-associated neurodegenerative disease is characterized by a single nucleotide polymorphisms (SNPs) or mutation in Trem2 or ApoE affecting microglial functions, the method comprising:
 administering to the subject a therapeutically effective amount of a composition comprising a microglial rescuing agent, wherein the microglial rescuing agent is one or more of a creatine, a creatine analog, a Dectin-1 agonist or pharmaceutically acceptable salt thereof.   
     
     
         10 . The method of  claim 9 , wherein a therapeutically effective amount of a microglial rescuing agent in one or more of improved microglial metabolic activity, decreased microglial autophagy, reduced neurite dystrophy, decreased cell death, improved microglia viability or improved microglia numbers. 
     
     
         11 . The method of  claim 9 , wherein the microglial dysfunction-associated neurodegenerative disease is Alzheimer's disease. 
     
     
         12 . The method of  claim 11 , wherein the therapeutically effective amount of a microglial rescuing agent results in improved microglia clustering around Aβ plaques or reduced plaque-associated neurite dystrophy. 
     
     
         13 . The method of  claim 9 , wherein the microglial rescuing agent is one or more of creatine, nicotinamide mononucleotide, cyclocreatine, phosphocyclocreatine, Zymosan, and Zymosan Depleted. 
     
     
         14 . The method of  claim 9 , wherein the subject has TREM2 deficient cells in the brain prior to administration of the microglial rescuing agent. 
     
     
         15 . The method of  claim 9 , wherein the subject is human. 
     
     
         16 . A method of treating at least one symptom of cognitive dysfunction in a subject having a microglial dysfunction-associated neurodegenerative disease, wherein the microglial dysfunction-associated neurodegenerative disease is characterized by a single nucleotide polymorphisms (SNPs) or mutation in Trem2 or ApoE affecting microglial functions, the method comprising:
 administering to the subject a therapeutically effective amount of a composition comprising a microglial rescuing agent, wherein the microglial rescuing agent is one or more of a creatine, a creatine analog, a Dectin-1 agonist or pharmaceutically acceptable salt thereof.   
     
     
         17 . The method of  claim 16 , wherein at least one symptom comprises short term memory function. 
     
     
         18 . The method of  claim 16 , wherein the at least one symptom comprises a spatial learning dysfunction. 
     
     
         19 . The method of  claim 16 , wherein the microglial rescuing agent is one or more of creatine, nicotinamide mononucleotide, cyclocreatine, phosphocyclocreatine, Zymosan, and Zymosan Depleted. 
     
     
         20 . The method of  claim 16 , wherein the subject is human.