Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau.

PROJECT SUMMARY (Description) Hyperphosphorylated tau is the major component of neurofibrillary tangles existing in the brains of Alzheimer’s Disease patients, but whether soluble hyperphosphorylated tau oligomers are already toxic to neurons, and if so, through what mechanisms, have remained unclear. This is largely due to the lack of experimental system to tackle these questions directly. This project will test the hypothesis that hyperphosphorylated tau oligomers promote neurotoxicity before the formation of insoluble tau fibrils, which is amplified by Ab peptides and/or the ApoE4 allele, but either apomorphine and raloxifene treatment mitigates these deleterious effects. This project has three specific aims. Aim 1 will compare the effects of intrahippocampal injection of tau and hyperphosphorylated tau (hyper-ptau) in wildtype and AD-mutant mice (J20 and ApoE KI). We will also compare the onset of behavioral/histological deficit and insoluble tau fibrils in these mice after intrahippocampal injection. Aim 2 will test the effects of hyper-ptau on the viability, mitochondrial functions, and axonal trasnport of cultured neurons. We will also confirm mitochondrial dysfunctions after brain injection of hyper-ptau in vivo. Aim 3 will test the protective effects of apomorphine and raloxifene in preventing hyper-ptau-induced toxicity and cognitive deficits in mice. Both compounds attenuates ptau aggregation in vitro and have a high potential to be repurposed for clinical treatment of AD.