We compared 2-week-old and 2-year-old NMRs since tau protein from these ages greatly differs in size and appropriately represent development and adulthood, respectively (Fig. tau protein is 88kDa, much larger than 45-68kDa tau expressed in other mammals. We propose that this 88kDa tau protein may offer exceptional microtubule stability and neuroprotection against lifelong elevated A. Keywords: Tau, phosphorylation, Alzheimer’s disease, naked mole-rat, aging, animal model == 1 . Introduction == The microtubule associated protein tau regulates several distinct neuronal processes including microtubule nucleation, polymerization, polarity, dynamics, spacing and bundling. Tau’s functional importance becomes evident in patients with microdeletions in the coding gene, MAPT. While exceedingly rare, these mutations result in mental retardation and craniofacial abnormalities (Rovelet-Lecrux and Campion, 2012). Correspondingly, mice homozygous forMaptdeletion display long term-potentiation impairments resulting in cognitive deficits (Ahmed, et al., 2014). Far more frequently, tau negative regulation occurs through post-translational phosphorylation (Lindwall and Cole, 1984), and tau misprocessing, initiated primarily through hyperphosphorylation, coincides with neurodegeneration in a variety of disorders (e. g., Pick’s disease, argyrophilic grain disease, progressive supranuclear palsy, frontotemporal dementia and chronic traumatic encephalopathy as well as Alzheimer’s disease (AD)) (Spillantini and Goedert, 2013). Several studies have revealed TNF exacerbated pathology in respective animal models upon genetically ablatingMaptincluding enhanced tauopathy (Ando, et al., 2011); lysosomal dysfunction (Pacheco, et al., 2009); Parkinsonism (Lei, et al., 2012) as well as A-associated axonal degeneration (Dawson, et al., 2010) underscoring the importance of functional tau during situations of neurotoxic stress. The vast majority of patients afflicted with tauopathies develop the diseases sporadically, with age being the greatest risk factor. Incongruously, the Aliskiren (CGP 60536) most common animal models for these diseases are short-lived mice that do not naturally develop tauopathy, possibly due to their short-lifespan. To overcome this shortcoming, induction of pathology is accomplished through genetic overexpression of mutant human gene variants. Fully penetrant AD-inducing mutations, while exceedingly rare accounting for <2% of all AD cases, Aliskiren (CGP 60536) occur in genes encoding proteins responsible for the accumulation of toxic, aggregation prone A1-42. The concomitant misprocessing of tau, cognitive decline, behavioral changes, neuronal loss and brain atrophy suggests that A, alone, may drive AD. Discovery of these familial AD mutations engendered the A hypothesis (Hardy and Higgins, 1992) that posits A accumulation is necessary and sufficient to drive AD pathogenesis and tauopathy. Many AD models expressing elevated A display cognitive impairments, but do not develop appreciable tau pathology unless multiple transgenes (e. g. mutant human tau, (Oddo, et al., 2003)) are also expressed and neurodegeneration seldom occurs (Wirths and Bayer, 2010). Strikingly, despite successful pharmacological amelioration of AD pathology and attenuation of cognitive decline over 300 times in such animal models, none of these promising preclinical findings have translated into effective and safe human therapies (Zahs and Ashe, 2010). The reasons, while not entirely clear, may reflect the modeling of the extremely rare heritable diseases in short-lived mammals, rather than addressing the more common sporadic nature of tauopathy and the use of model systems with lifespans long enough to track pathogenesis. Recently we discovered naturally expressed, high levels of A in the brains of the naked mole-rat (NMR, Heterocephalus glaber), the longest lived rodent known (Edrey, et al., 2013). These mouse-sized rodents defy maximum lifespan predictions by living ~5 times longer than expected based on their body size and ~8 times longer than similar sized mice. With a maximum lifespan of > 30 years, they offer an exceptional perspective to investigate age-associated Aliskiren (CGP 60536) diseases. Many NMRs express higher brain A levels than do 3xTg-AD mice (Edrey, et al., 2013), a well-characterized mouse model of AD pathology genetically manipulated to express high levels of this toxic peptide (Oddo, et al., 2003). The NMR A peptide differs from that of human A by one amino acid, but both human and NMR A exert similar neurotoxicity to mouse cortical neuronsin vitro(Edrey, et al., 2013). NMRs, however , do not develop manifest plaques and seemingly maintain neuronal integrity. We wondered whether tau metabolism remained properly regulated despite > 30 years of high levels of A peptide. Specifically we Aliskiren (CGP 60536) investigated whether NMR tau protein is similar to human tau (e. g., sequence, size, expression, phosphorylation), how it changes with age, and whether lifelong elevated levels of Aliskiren (CGP 60536) A alter tau misprocessing in NMRs. We assessed levels of total tau, phosphorylated tau and known tau kinases throughout the NMR 30-year lifespan and compared adult brain histology to that of well-characterized 3xTg-AD mice. == 2 . Materials and Methods == == 2 . 1 Animals == Animal procedures were carried out in adherence to NIH, Federal, State, and Institutional guidelines.