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

Rossi, Francesca; Geiszler, Philippine C.; Meng, Weina; Barron, Matthew; Prior, Malcolm; Herd-Smith, Anna; Loreto, Andrea; Yanez Lopez, Maria; Faas, Henryk; Pardon, Marie-Christine; Conforti, Laura

Authors

Francesca Rossi

Philippine C. Geiszler

Weina Meng

Matthew Barron

Malcolm Prior

Anna Herd-Smith

Andrea Loreto

Maria Yanez Lopez

Henryk Faas

Marie-Christine Pardon

Laura Conforti laura.conforti@nottingham.ac.uk

Abstract

NAD metabolism and the NAD biosynthetic enzymes nicotinamide nucleotide adenylyltransferases (NMNATs) are thought to play a key neuroprotective role in tauopathies, including Alzheimer’s disease. Here, we investigated whether modulating the expression of the NMNAT nuclear isoform NMNAT1, which is important for neuronal maintenance, influences the development of behavioral and neuropathological abnormalities in htau mice, which express non-mutant human tau isoforms and represent a model of tauopathy relevant to Alzheimer’s disease. Prior to the development of cognitive symptoms, htau mice exhibit tau hyperphosphorylation associated with a selective deficit in food burrowing, a behavior reminiscent to activities of daily living which are impaired early in Alzheimer’s disease. We crossed htau mice with Nmnat1 transgenic and knockout mice and tested the resulting offspring until the age of 6 months. We show that overexpression of NMNAT1 ameliorates the early deficit in food burrowing characteristic of htau mice. At 6 months of age, htau mice did not show neurodegenerative changes in both the cortex and hippocampus, and these were not induced by downregulating NMNAT1 levels. Modulating NMNAT1 levels produced a corresponding effect on NMNAT enzymatic activity but did not alter NAD levels in htau mice. Although changes in local NAD levels and subsequent modulation of NAD-dependent enzymes cannot be ruled out, this suggests that the effects seen on behavior may be due to changes in tau phosphorylation. Our results suggest that increasing NMNAT1 levels can slow the progression of symptoms and neuropathological features of tauopathy, but the underlying mechanisms remain to be established.

Journal Article Type Article
Publication Date Feb 26, 2018
Journal Behavioural Brain Research
Print ISSN 0166-4328
Electronic ISSN 1872-7549
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 339
DOI https://doi.org/10.1016/j.bbr.2017.11.030
Keywords Alzheimer’s disease (AD), htau, NMNAT1, NAD, food burrowing, MRS
Publisher URL http://www.sciencedirect.com/science/article/pii/S0166432817316364?via%3Dihub
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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