PET Imaging to Evaluate a Novel Chemokine Antagonist to Protect Synapses in ADRD

7. Project Summary ADRD dementias account for up to 25% of all dementias in patients older than 65 years and there is strong evidence of co-morbid pathologies caused by (amyloid β (Aβ), tau and α-synuclein (αSyn). The degree of AD- related pathology in Lewy Body Dementias (LBD) is moderate or severe in 50% of PDD and more than 70% of DLB patients have concomitant AD-related pathology so that these patients experience a more heterogeneous, faster, and severe clinical phenotype. Cognitive impairment is closely associated with synapse loss which occurs significantly prior to neuronal loss suggesting that synaptic dysfunction is the key treatment target and that ultimately synapse loss by multiple toxic oligomers (αSyn, Aβ, and tau), that begins with their binding to PrPc, must be stopped. Our results show that RAP-103, a small oral peptide CCR5 antagonist potently prevents both αSyn and Aβ-mediated spine and synapse loss in rodent and human neurons by blocking PrPc activation that disrupts microtubules, spine structure and synapse function. RAP-103 protected rodent and human neuron spines and synapses from αSyn and Aβ-induced loss, and in a pilot study of the human αSyn expressing animal model Line 6116, prevented cognitive deficits. By binding to neuronal CCR5, RAP-103 exerts an allosteric inhibitory effect on membrane bound PrPc/NOX complex activation to block multiple toxic oligomers to stop, possibly reverse, synapse loss and cognitive decline in ADRD including LBD. Utilizing the Tg4510 mixed α- Syn/Tauopathy animal model we will conduct a definitive in vivo study of RAP-103 protective effects on synapse density and disease biomarkers relevant to ADRDs by brain histochemical analysis. We will compare in vivo histochemical analysis of synapse density to live animal SV2A PET imaging with [18F]SynVesT-1 as a quantitative biomarker of synaptogenesis. We will administer RAP-103 by oral dosing from months 6 to 7 when animals experience synapse loss. We will determine RAP-103 effects on markers of brain synapse density in cortex and hippocampus by quantitative methods measuring expression of Synaptophysin 1, a synaptic vesicle protein and SVA2, the target of the PET imaging tracer and normalize to total neuron density with NeuN in pre- identified regions of interest. We will also determine RAP-103 effects on disease biomarkers by measuring the number of neurofibrillary tangles-NFT load, oligomeric Tau, pThr231Tau, Multimeric total αSyn and pSer129 αSyn. Successful completion of the Aims will support further development of RAP-103 for synapse protecting effects and suggest using SV2A PET imaging with [18F]SynVesT-1 as a quantitative biomarker of synaptogenesis in ADRDs, which can then be correlated with biomarkers and cognitive benefits for use in human testing.