Tau protease compositions and methods

Abstract

Tau protein has a causative role in Alzheimer's disease and multiple other neurodegenerative disorders exhibiting tau histopathology collectively termed tauopathies. The primary function of tau protein is to facilitate assembly and maintenance of microtubules in neuronal axons. In the disease process tau protein becomes modified, loses its affinity to microtubules and accumulates in the cell body where it forms aggregates. The large neurofibrillary tangles formed from tau protein assembled into filaments were thought to be the pathological structure of tau. However, more recent work indicates that smaller, soluble oligomeric forms of tau are best associated with neuron loss and memory impairment. A novel and unexpected protease activity has been discovered to be associated with tau in oligomeric but not monomeric structures. Methods have been developed to form and purify tau protease and to assay its activity. Tau protease activity constitutes a totally novel mechanism for tau-mediated neurodegenerative disease by causing tau loss of function, as it cleaves itself, and gain of toxic function as it can cleave other proteins and facilitate cell death through apoptotic and/or senescence pathways. Tau protease presents a novel and unique target for the development of therapeutics that may be achieved by several strategies including by inhibiting the tau oligomer enzymatic activity.

1 . A tau protease associated with AD. 
     
     
         2 . (canceled) 
     
     
         3 . A protease inhibitor that inhibits or blocks tau protease activity. 
     
     
         4 . A protease inhibitor of  claim 3 , wherein the protease inhibitor is a cysteine protease inhibitor. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A composition comprising tau oligomer having a staggered alignment comprising one or two free thiol moieties from a cysteine amino acid of the tau oligomer, wherein the tau oligomer comprises 3R or 4R isoforms of tau monomer. 
     
     
         13 . (canceled) 
     
     
         14 . A composition comprising tau protease, wherein the tau oligomer protease is a cysteine protease. 
     
     
         15 . A composition according to  claim 14 , wherein the cysteine protease is adapted for screening drug compounds that enhance or inhibit the tau oligomer proteolytic activity, wherein the tau monomeric unit comprises SEQ ID NO. 1-6. or derivatives. 
     
     
         16 . A composition according to  claim 15 , wherein the cysteine protease is inhibited by a cysteine protease inhibitor that blocks or prevents its activity and is useful in treating tauopathies or Alzheimer's disease. 
     
     
         17 . A composition according to  claim 15 , wherein the tau oligomer protease cleaves tau oligomer to form tau cleavage products and the tau cleavage products function as biomarkers for tauopathies or Alzheimer's disease. 
     
     
         18 . A composition according to  claim 17 , wherein the cysteine protease comprises 4R tau oligomer, 4R and 3R tau oligomer or a combination thereof. 
     
     
         19 . A composition comprising extracellular tau oligomer protease, wherein the extracellular tau oligomer protease is a target for immunotherapy. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A cleavage product of tau protein, wherein the cleavage product is formed from tau protease and the cleavage product comprises fragments of tau oligomer, and the tau oligomer is in at least one conformation comprising tau dimer, tau trimer, tau tetramer, tau pentamer, tau hexamer, tau septamer, tau octamer, tau nonamer, tau decamer, tau unadecamer, tau dodecamer, 3R tau, 4R tau, or mixtures of 3R tau and 4R tau or a combination thereof. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled)