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

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

doi:10.1016/j.bbr.2017.11.030

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.

Highlights

NAD metabolism is increasingly implicated in a variety of biological functions, including regulation of gene transcription, lifespan, cell death, circadian rhythm and glucose homeostasis [1,2]
Cytoplasmic NMNAT2 has been recently described as an axon survival factor, a role which is linked to its enzymatic activity, while NMNAT1 appears to have a similar function in neuronal cell bodies [6]
NMNAT1 deficiency does not contribute to food burrowing impairment in htau/mtau+/− mice, but NMNAT1 overexpression rescues this deficit

Summary

Introduction

NAD metabolism is increasingly implicated in a variety of biological functions, including regulation of gene transcription, lifespan, cell death, circadian rhythm and glucose homeostasis [1,2]. The three mammalian isoforms of the central NAD biosynthetic enzyme, nicotinamide mononucleotide adenylyltransferases (NMNATs), have recently emerged as crucial players in neuronal maintenance and protection [3,4,5,6]. They share the same enzymatic activity but a different subcellular distribution [7,8]. The discovery that loss-of-function mutations in the nuclear isoform NMNAT1 cause Leber Congenital Amaurosis (LCA), a human nervous system disorder characterized by degeneration of retinal neurons and blindness [9,10,11], directly links NMNAT1 to neuron survival. In Drosophila a single, homogenously distributed NMNAT isoform has been reported, whose loss causes neuronal and axonal degeneration [3]

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