Kanninen K, Malm TM, Jyrkkänen HK, Goldsteins G, Keksa-Goldsteine V, Tanila H, Yamamoto M, Ylä-Herttuala S, Levonen AL, Koistinaho J. Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci. 2008 Nov;39(3):302-13. PubMed.
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I see two very interesting insights in this new paper. First, the protective role of Nrf2 has been so far thought to be mediated within astrocytes; this paper shows clearly that when expressed only in neurons, Nrf2 is still protective. Second, when the neurons are protected, the degree of reactive astrocytosis is less, yet the degree of microglial activation was not affected. That's interesting because it is not clear what triggers reactive astrocytosis. Is it activated microglia or injured neurons, or something else? So the finding here that reactive astrocytosis abates when microglial activation does not implies that activated microglia alone may not be the sole or primary cause of reactive astrocytosis, but rather that the astrocytes are sensing neuronal signals or lack of neuronal signals. Lastly, an interesting question raised by these findings is whether the improved spatial learning is explained by Nrf2's effects in neurons alone or whether the lessened reactive gliosis also contributed to the behavioral improvements. Clearly it will be very interesting to further understand how NRF2 is acting in the neurons.
This new publication on Nrf2 activation in hippocampal neurons and modulation of spatial learning and memory in a mouse model of Alzheimer disease is quite intriguing. Neuron-specific Nrf2 overexpression is a novel approach. My laboratory has avoided this approach due to our lack of understanding as to why basal Nrf2-ARE activity is absent in most differentiated neuronal populations with the exception of dopaminergic and some spinal motor neurons. The findings in this paper, however, are encouraging in that neurons transduced with Nrf2 survive, maintain normal function, and actually have improved functionality, not only in the APP/PS1 mice, but also in wild-type mice.
The evidence for suppression of astrogliosis without affecting microgliosis is also very interesting. It suggests that information is being exchanged between the different cells types that can modulate disease pathogenesis. Our work using transgenic approaches to overexpress Nrf2 in astrocytes has also shown positive outcomes in mutant hSOD1 models of amyotrophic lateral sclerosis (Vargas et al., 2008) and the MPTP model of Parkinson disease (Chen et al., 2009), as well as chemical and genetic models of Huntington disease (unpublished data).
These data, in combination with this present work from Dr. Koistinaho’s laboratory, strongly suggest that modulation of Nrf2 activity simultaneously in different cell types could have synergistic neuroprotective effects by targeting different key components driving cellular dysfunction. Therefore, distinguishing the role(s) of enhanced Nrf2 activity in astrocytes, neurons, and microglia, and understanding how Nrf2 modifies communication among these cell types in models of ALS, Parkinson, Huntington, and Alzheimer diseases are critical to understanding Nrf2-mediated neuroprotection.
References:
Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA. Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci. 2008 Dec 10;28(50):13574-81. PubMed.
Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA. Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: Critical role for the astrocyte. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2933-8. PubMed.
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