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 (ß-amyloid and tau oligomers), Fronto-temporal lobe
dementia (tau oligomers), and Parkinson’s Disease (a-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 ß-amyloid (Aß) oligomers and tau
oligomers therein. The critical importance of addressing the oligomeric forms of Aß and tau in AD pathogenesis,
along with the failure of many clinical studies using anti-Aß aggregating drugs, highlight the need for new,
innovative therapies. Since 2007, 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 Aß oligomerization/aggregation, both inside and outside
neurons. These anti-aggregating effects demonstrate that TEMT penetrates the brain parenchyma and neurons
to destabilize Aß 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 1 will utilize
assays for oligomeric forms of Aß, tau, and a-synuclein to specifically measure TEMT’s effects on each of these
three toxic oligomers in CSF samples placed within a human head mannequin. Aim 2 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: 1) investigating the “indirect” effects of TEMT in neuronal cell
cultures over-expressing these oligomers and 2) 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 2016 that involves our current set of TEMT parameters.