NAD-biosynthetic enzyme NMNAT1 reduces early behavioral impairment in the htau mouse model of tauopathy

Abstract

HighlightsFirst investigation of the role of NMNAT1 in the early stage of tauopathies in mice.htau mice display a robust deficit in food burrowing prior to onset of cognitive symptoms.NMNAT1 overexpression rescues this behavioral abnormality.

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

“…On the other hand, increasing 4R tau and decreasing 3R tau expression without altering total tau levels was found to worsen tau pathology and associated behavioral deficits in hTau mice (47). And although removal of mTau was found necessary for the tau pathology to occur in hTau mice (36), we have shown previously that heterozygous deletion of mTau is sufficient for robust behavioral deficits and tau phosphorylation to occur in this model (48). While these data show that direct modulation of the 4R:3R ratio in the brain of hTau mice alters tau pathology, whether or not this also affects susceptibility to systemic inflammation and LPS-induced changes in tau phosphorylation is currently not known.…”

“…We have previously shown that hTau mice bred on a heterozygous mTau knockout background develop behavioral and pathological features of tauopathies (48). Using hemibrains from 9-month-old mice, we first aimed to determine whether this breeding strategy impacted on tau aggregation, but neither hTau/mTau +/− nor hTau/mTau −/− mice exhibited aggregated tau (Supplementary Figure 1G).…”

“…Here, we first report that increased 4R tau levels in hTau/mTau +/− mice exacerbate tau hyperphosphorylation compared to hTau mice on a full mTau knockout background (hTau/mTau −/− ). Since systemic inflammation is expected to be an early event in the pathogenesis of AD, we used 3-month-old mice, corresponding to the onset of behavioral changes in these models (48,49). We also report that increasing 4R tau availability was associated with a rapid reduction in tau phosphorylation in the hippocampus, seen 4 h after inoculation with low doses of LPS, and persisting for at least 24 h.…”

MicroRNA miR-1002 enhances NMNAT-mediated stress response by modulating alternative splicing

“…NMNAT has been shown to protect many species against a variety of stresses, including heat, hypoxic, oxidative, proteotoxic, and aging stress (Ali et al, 2012;Liu et al, 2018;Miwa et al, 2017;Rossi et al, 2018;Ruan et al, 2015;Zhou et al, 2016). Furthermore, it has previously been reported that NMNAT is a stress response gene regulated by the stress transcription factor HSF (Ali et al, 2011).…”

“…Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a housekeeping enzyme long been known as the master enzyme in nicotinamide adenine dinucleotide (NAD + ) biosynthesis in all living organisms (Zhai et al, 2009). In addition, NMNAT proteins are essential for neuronal maintenance and protection (Ali et al, 2012;Brazill et al, 2017;Fang et al, 2012;Kitaoka et al, 2013;Press and Milbrandt, 2008;Rossi et al, 2018;Sasaki and Milbrandt, 2010;Sasaki et al, 2009;Wen et al, 2011;Yan et al, 2010;Zhai et al, 2006Zhai et al, , 2008. NMNAT has been shown to confer robust resistance to various stressors across many species, including hypoxia (Ali et al, 2011;Wen et al, 2013), heat (Ali et al, 2011), oxidative stress (Chiurchiù et al, 2016;Cobley et al, 2018), disease states (Ali et al, 2012;Rossi et al, 2018;Ruan et al, 2015;Zhai et al, 2008), and aging .…”