Disaggregation of Toxic Protein Oligomers in Brain with Electromagnetic Treatment

ABSTRACT Formation of misfolded protein oligomers in neurons is an early and causative event in a variety of neurodegenerative diseases such as Alzheimer s Disease amyloid and tau oligomers Fronto temporal lobe dementia tau oligomers and Parkinson s Disease synuclein oligomers These toxic oligomers share a common aggregation mechanism that involves formation of hydrogen bonds between individual monomers A therapeutic that can disaggregate these oligomers or prevent their formation from monomers could therefore have extraordinary potential to treat a host of neurodegenerative diseases disorders Regarding Alzheimer s Disease AD currently available therapeutics e g AChE inhibitors and memantine only temporarily slow the rate of cognitive decline without affecting the disease process This may be in large part because these drugs have not been shown to penetrate the brain s neurons to disaggregate toxic amyloid A oligomers and tau oligomers therein The critical importance of addressing the oligomeric forms of A and tau in AD pathogenesis along with the failure of many clinical studies using anti A aggregating drugs highlight the need for new innovative therapies Since Dr Gary Arendash NeuroEM s PI and his collaborators have been developing and testing a new non pharmacologic intervention against AD Transcranial Electromagnetic Treatment TEMT In multiple peer reviewed papers he has demonstrated in both in vitro and in vivo studies using AD transgenic mice that TEMT prevents and reverses A oligomerization aggregation both inside and outside neurons These anti aggregating effects demonstrate that TEMT penetrates the brain parenchyma and neurons to destabilize A aggregates The result is a prevention reversal of cognitive deficits in AD transgenic mice This proposal s Aims will focus on administering TEMT through a new prototype head device developed for human TEMT administration against AD To effectively validate and greatly extend our approach Aim will utilize assays for oligomeric forms of A tau and synuclein to specifically measure TEMT s effects on each of these three toxic oligomers in CSF samples placed within a human head mannequin Aim will then seek to optimize the TEMT parameters for maximum anti oligomerization and investigate direct mechanisms of TEMT action The successful execution of these Aims will provide validation of the direct anti oligomerization effects of TEMT across toxic proteins involved in multiple neurodegenerative diseases In a follow up SBIR Fast Track application NeuroEM will continue this work by investigating the indirect effects of TEMT in neuronal cell cultures over expressing these oligomers and performing a Phase II clinical trial involving TEMT administration to AD patients utilizing the optimal set of TEMT parameters Thus the extent of both direct and indirect TEMT actions across multiple pathologic oligomers will be determined as will insight into the anti oligomerization mechanisms of TEMT action all this utilizing a TEMT head device that we will utilize in a Phase I AD clinical trial starting in Summer that involves our current set of TEMT parameters NARRATIVE Alzheimerandapos s Disease AD is a neurodegenerative disease that primarily affects individuals over years of age and is characterized by a progressive loss of memory due to the loss and dysfunction of neurons in brain areas important for cognition In an estimated million Americans had Alzheimerandapos s disease AD which accounts for percent of all cases of dementia The formation of misfolded protein oligomers in neurons is an early and causative event in a variety of neurodegenerative diseases including AD Current therapeutics against AD e g AChE inhibitors and memantine only temporarily slows the rate of cognitive decline without affecting the disease process or addressing the oligomeric forms of amyloid A and oligomeric tau in AD pathogenesis NeuroEM has been developing and testing a new non pharmacologic intervention against AD Transcranial Electromagnetic Treatment TEMT which disaggregates A oligomers This grant application will determine the anti oligomerization effects of TEMT on three toxic oligomers A tau and synuclein optimize TEMT treatment parameters and investigate TEMT s direct mechanism s of action all of which are important for refining TEMT technology as NeuroEM moves into clinical trials with this promising neuromodulatory technology