Alzheimer's disease (AD) and AD-related dementias (ADRD) affect more than 40 million people worldwide causing major disability in patients with an impairment of cognitive function and changes in social behavior. A large subset of ADRD patients presents with frontotemporal lobar degeneration (FTLD) and widespread deposition of hyperphosphorylated tau protein (p-tau; FTLD-TAU), which also accumulates in patients with AD. Despite the high prevalence of these tauopathies, mechanisms of neurodegeneration are only partially understood and curative treatment options still do not exist. There is growing evidence that non-cell-autonomous mechanisms of neuronal degeneration play an important role during disease development and that neurons, glial and inflammatory cells significantly contribute to pathologic changes in patients' brains via direct cell-cell contacts, secreted factors and deposition of soluble and insoluble molecules within and outside cells. Important work has shown neuron-to-neuron propagation of pathological tau protein in models of AD that significantly contributes to neurodegeneration at sites of spread and tau accumulation. Our study sets out to determine the effects of aggregated tau protein on the metabolism in patient neurons in a dynamic human stem cell model of tauopathy both in vitro and in vivo. Encouraged by our preliminary data, we hypothesize that energy fuels such as glucose, amino acids and especially fatty acids are used differently in patient neurons compared to control (Ctrl) cells under basal conditions and when exposed to sarkosyl-insoluble tau filaments. We will use differentiated induced pluripotent stem cells (iPSCs) carrying the AD-associated V717I (London) mutation in APP (amyloid precursor protein, APPV717I) or the FTLD-TAU-associated N279K mutation in MAPT (MAPTN279K) as a model for tauopathy. Phenotypes in these cells will be compared to those in isogenic Ctrl cells. We will test our hypothesis of tau filament-mediated alteration of cellular programs and metabolic states in patient neurons in two specific aims by applying stress assays, mass spectrometry for metabolites as well as single nucleus RNA sequencing on neuron/neuron co-cultures and on mixed grafts 10 weeks after transplantation into the brains of adult immunocompromised mice.
This study sets out to investigate the role of purified tau filaments on neuronal degeneration in a stem cell model of tauopathies using patient-derived and mutant induced pluripotent stem cells as well as gene- corrected, isogenic control cells. Our preliminary data show that tau filaments significantly alter metabolic states in cultured patient neurons. To further evaluate the mechanism of filament-mediated changes, we will apply stress assays, mass spectroscopy for metabolites as well as single nucleus RNA sequencing on neuron/neuron co-cultures and on mixed grafts 10 weeks after transplantation into the brains of adult immunocompromised mice.