Nmnat2 Attenuates Tau Phosphorylation Through Activation of PP2A

Abstract

The activity of protein phosptase-2A (PP2A) is significantly decreased in the brains of Alzheimer's disease (AD) patients, but the upstream effectors for regulating PP2A activity are not fully understood. Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) is a key enzyme involved in energy metabolism and its gene expression level is reduced in AD brain specimens. Whether Nmnat2 can activate PP2A deserves to be explored. Here, we first measured the level of Nmnat2, Tyr307-phosphorylation of PP2A, and tau phosphorylation in Tg2576 mice. We observed that the mRNA and protein levels of Nmnat2 were significantly decreased with a simultaneous elevation of p-Tyr307-PP2A and tau phosphorylation in Tg2576 mice. Further studies in HEK293 cells with stable expression of human tau441 (HEK293/tau) demonstrated that simultaneous inhibition of PP2A by okadaic acid abolished the Nmnat2-induced tau dephosphorylation. Moreover, we further demonstrated that overexpression of Nmnat2 could activate PP2A with attenuation of tau phosphorylation, whereas downregulation of Nmnat2 by shRNA inhibited PP2A with tau hyperphosphorylation at multiple AD-associated sites. Our data provide the first evidence that Nmnat2 affects tau phosphorylation by regulating PP2A activity, suggesting that Nmnat2 may serve as a potential target in arresting AD-like tau pathologies.

Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans?

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Nmnat1 protects neuronal function without altering phospho‐tau pathology in a mouse model of tauopathy

“…In drosophila models of tauopathy, dNmnat overexpression mitigates tau pathology, perhaps by directly targeting phospho‐tau species to the proteasome . In mammalian systems, overexpression of Nmnat2 mitigates tau phosphorylation in HEK293 cells in a PP2a‐dependent manner . Likewise, Nmnat2 overexpression in a mouse model of accelerated tauopathy (rTg4510) prevented cortical neuron loss and reduced the accumulation of phosphorylated tau, although detailed immunohistochemical examination of tau pathology was not performed .…”

Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer’s disease

“…Conversely, betaine and nicotinamide mononucleotide adenylyltransferase 2 can activate PP2A and attenuate tau hyperphosphorylation [29,30] . In the astrocytes of tg2567 mice, a widely-used amyloidogenic model of AD, PP2A is activated.…”