Peripheral Neuroinflammation and Novel Potential Therapeutic Targets in Familial Amyloidotic Polyneuropathy

.........................................................................................................................17 Resumo ..........................................................................................................................19 General Introduction ......................................................................................................21 Transthyretin ...............................................................................................................23 Transthyretin gene structure and dynamics .................................................................23 Transthyretin structure ................................................................................................25 Transthyretin physiological functions ...........................................................................27 Transthyretin as a transporter protein .....................................................................27 Transthyretin as a novel protease ...........................................................................29 Transthyretin in the nervous system .......................................................................29 Other functions of transthyretin ...............................................................................31 Transthyretin molecular variants ..................................................................................31 Familial Amyloidotic Polyneuropathy ...........................................................................32 Pathological features of Familial Amyloidotic Polyneuropathy .....................................33 Mechanisms for transthyretin amyloidogenesis ...........................................................35 Composition of transthyretin amyloid deposits .............................................................36 Animal models of human amyloidoses ........................................................................38 Mechanisms for cytotoxicity in Familial Amyloidotic Polyneuropathy ...........................41 Endoplasmic reticulum stress and the unfolded protein response ...........................42 Apoptosis and mitochondrial dysfunction ................................................................44 Heat shock response ..............................................................................................46 Extracellular matrix remodeling ...............................................................................47 Inflammation and oxidative stress ...........................................................................47 Therapies for Familial Amyloidotic Polyneuropathy ......................................................51 Liver transplantation .................................................................................................51 Gene therapy ............................................................................................................52 Stabilization of transthyretin tetramers ...................................................................... 53 Fibrils disrupters and amyloid clearance ................................................................... 54 Anti-oxidant and anti-apoptotic treatments ............................................................... 55 Peripheral nerve regeneration ...................................................................................... 57 Wallerian degeneration ................................................................................................ 57 The role of Schwann cells in Wallerian degeneration ............................................... 59 The immune cell response to peripheral nerve injury ................................................ 62 Injury signaling to the cell body................................................................................. 64 Axonal elongation ..................................................................................................... 66 Final remarks ............................................................................................................... 67 Research Project ........................................................................................................... 69 Research Goals ............................................................................................................. 71 Chapter I......................................................................................................................... 73 A novel nanoparticle delivery system for in vivo targeting of the sciatic nerve: evaluation of heparan sulfate influence on transthyretin deposition ........................ 73 Chapter II........................................................................................................................ 95 The inflammatory response to sciatic nerve injury in a Familial Amyloidotic Polyneuropathy mouse model ..................................................................................... 95 Chapter III ..................................................................................................................... 125 Interleukin-1 signaling pathway as a therapeutic target in transthyretin amyloidosis ...................................................................................................................................... 125 Chapter IV .................................................................................................................... 145 Protective role of Anakinra against transthyretin mediated axonal loss and cell death in a mouse model of Familial Amyloidotic Polyneuropathy .......................... 145 Chapter V ..................................................................................................................... 173 Glial cells in Familial Amyloidotic Polyneuropathy .................................................. 173 Conclusions and Future Perspectives ....................................................................... 195 References ................................................................................................................... 201 Annex ........................................................................................................................... 231