7. Project Summary There is strong evidence of co-morbid pathologies (α-synuclein, amyloid β, tau) in age-related dementias that cause synergistic contributions to neurodegeneration such that patients exhibit a more severe and rapid disease progression. Simultaneous treatment of multiple proteinopathies commonly occurring in these patients (a largely ignored strategy) will be required to effectively treat ADRDs such as LBDs, which account for up to 25% of all dementias in patients older than 65 years. There are currently no disease-modifying treatments for these patients. Synapse loss is the principal cause of memory and cognitive decline in various dementias and occurs significantly prior to neuronal loss. Our scientific premise is that effective treatments for LBD needs to mitigate synapse loss caused by α-Syn, Aβ, and tau activation of a well-known PrPc/NOX dependent mechanism involving actin/cofilin-rod formation that leads to disruption of cytoarchitecture followed by rapid loss of dendritic spines and synapses. Chemokine receptors of the innate immune system are also present on neurons and in our recent R43 we showed that two of their antagonists (both approved drugs) exert a negative allosteric effect, likely via physical interaction in membrane rafts, to suppress PrPc/NOX activation and subsequent synapse loss. This novel finding strongly suggests chemokine receptor antagonists as potential treatments for mixed- proteinopathy dementias. Our R43 results show that RAP-103, a CCR2/CCR5 antagonist, prevents and reverses both α-Syn and Aβ rodent and human synapse loss in vivo at pM doses and prevents cognitive deficits in an α- Syn transgenic animal model. In order to broaden the treatment targets to include tau effects we will conduct a definitive study of RAP-103 effects on LBD mixed-proteinopathy relevant biomarkers, disease markers, synaptic damage markers and correlate those with cognitive performance and restoration of functional synapses in Tg4510 tau/α-Syn mice. At 6 months, when animals show cognitive impairments, we will administer RAP-103 by oral dosing for 8 weeks, then determine performance in the Morris Water Maze test of spatial memory and learning. We will collect the brains to determine the effect of RAP-103 on oligomeric tau, pThr231 tau, multimeric total α-Syn and pSer129 αSyn, inflammation in microglia and astrocytes, cytokine and chemokine expression, and synapto-dendritic loss in in cortex and hippocampus. Immunoreactive area, density, mean signal, mean size and integrated optical density (IOD) of all objects with all markers will be blindly quantified by objective measures. We will determine the effect of RAP-103 on functional synapses determined from electrophysiological measurements in CA3 to CA1 region of hippocampus (ex vivo brain slice) from TG4510. The studies will provide go-no go quantifiable inflection points to decide further development. We have completed initial animal safety studies and have received a pre-I...