CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy

Abstract

Tauopathies, characterized by neurofibrillary tangles (NFTs) of phosphorylated tau proteins, are a group of neurodegenerative diseases, including frontotemporal dementia and both sporadic and familial Alzheimer's disease. Forebrain-specific over-expression of human tau(P301L), a mutation associated with frontotemporal dementia with parkinsonism linked to chromosome 17, in rTg4510 mice results in the formation of NFTs, learning and memory impairment and massive neuronal death. Here, we show that the mRNA and protein levels of NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), a recently identified survival factor for maintaining neuronal health in peripheral nerves, are reduced in rTg4510 mice prior to the onset of neurodegeneration or cognitive deficits. Two functional cAMP-response elements (CREs) were identified in the nmnat2 promoter region. Both the total amount of phospho-CRE binding protein (CREB) and the pCREB bound to nmnat2 CRE sites in the cortex and the hippocampus of rTg4510 mice are significantly reduced, suggesting that NMNAT2 is a direct target of CREB under physiological conditions and that tau(P301L) overexpression down-regulates CREB-mediated transcription. We found that over-expressing NMNAT2 or its homolog NMNAT1, but not NMNAT3, in rTg4510 hippocampi from 6 weeks of age using recombinant adeno-associated viral vectors significantly reduced neurodegeneration caused by tau(P301L) over-expression at 5 months of age. In summary, our studies strongly support a protective role of NMNAT2 in the mammalian central nervous system. Decreased endogenous NMNAT2 function caused by reduced CREB signaling during pathological insults may be one of underlying mechanisms for neuronal death in tauopathies.

The NAD+synthesizing enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) is a p53 downstream target

“…[52][53][54] Both NMNAT-2 and SIRT1 have been shown to maintain healthy axons and suppress various neurological disorders, including tauopathy, which is associated with Alzheimer disease. 52,[55][56][57][58] The present study adds an important piece (i.e., p53) to this complex puzzle, as it provides clues as to how NMNAT-2 and SIRT1 are functionally linked within the brain. Therefore p53-controlled expression of NNMAT-2 under stress conditions may play an important role in tauopathy and other types of neuronal diseases.…”

The endocannabinoid system in normal and pathological brain ageing

“…A crucial role of CREB signalling in memory formation was found in both invertebrates and vertebrates [30]. Generally, decreased CREB activity was associated with learning impairments in healthy aged animals [31,32] and with cognitive deficits in animal models of neurodegenerative disorders [33][34][35]. Importantly, the level of phosphorylated CREB and the activity-induced increase in CREB phosphorylation is diminished in ageing [36,37], and this itself may influence the ageing process [38,39].…”

PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2

“…NAD is an essential co-enzyme for several biological process, such as cell death, energy metabolism and calcium mobilization. NMNAT2 is highly expressed in the brain, and along with axon protection following injury (44)(45)(46)(47)(48)(49) is implicated in neurodegenerative disease (50)(51)(52)(53). While functional genetics indicate PHR proteins can inhibit NMNAT2, the biochemical mechanism by which this occurs remains untested.…”