Zhu Y, Hou H, Rezai-Zadeh K, Giunta B, Ruscin A, Gemma C, Jin J, Dragicevic N, Bradshaw P, Rasool S, Glabe CG, Ehrhart J, Bickford P, Mori T, Obregon D, Town T, Tan J. CD45 deficiency drives amyloid-β peptide oligomers and neuronal loss in Alzheimer's disease mice. J Neurosci. 2011 Jan 26;31(4):1355-65. PubMed.
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Comments
Indiana University School of Medicine
This is an interesting paper by Zhu and colleagues, who show that CD45 deletion in PSAPP transgenic mice exacerbates the amyloid pathology, increases pro-inflammatory cytokine production, and results in neuron loss. These findings add to the growing body of literature that serves to illustrate the dynamic complexity of the role of neuroinflammation, not only in Alzheimer's disease, but also in other neurodegenerative disorders. The observations, in many ways, mimic those observed by Carol Colton and myself when we deleted the NOS2 gene in APP transgenic mice (Wilcock et al., 2008). Taken together with the present data, these findings would indicate that transgenic mice require a shift in the normal inflammatory response to advance disease pathology to cause neurodegeneration. These data also support the concept that microglia are a critical component in the homeostasis between β amyloid production and clearance; this paper shows that CD45 deletion results in decreased phagocytosis of β amyloid by microglia.
While the authors suggest that pharmacological promotion of CD45-mediated microglial clearance of β amyloid could be a therapeutic strategy, this may be considerably difficult. The current data, in addition to the substantial body of data now published, show the sensitivity of the neuroinflammatory system. Perturbations to this system in either direction can clearly exacerbate pathology as opposed to reduce it. That is not to say that such an approach is impossible, but should be very carefully approached so as not to drive the inflammatory state to the opposite extreme causing further detrimental effects.
References:
Wilcock DM, Lewis MR, Van Nostrand WE, Davis J, Previti ML, Gharkholonarehe N, Vitek MP, Colton CA. Progression of amyloid pathology to Alzheimer's disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J Neurosci. 2008 Feb 13;28(7):1537-45. PubMed.
University of Southern California
Reply to comment by Donna Wilcock
I wanted to respond briefly to the thought-provoking comments by Donna Wilcock. We, too, were struck by the parallels between our study and her and Carol Colton’s work on NOS2 deletion in APP transgenic mice. It is striking that genetic ablation of very different molecules, which nonetheless both play key roles in negatively regulating microglial "activation," could result in exacerbation of AD-like pathology. This highlights the concept that, rather than being strictly "good" or "bad," neuroinflammation exists in a state of imbalance in the context of AD.
We also agree that one needs to be mindful and cautious of the delicate balance at play here when considering translational approaches toward pharmacotherapies targeting microglial activation. It seems in this regard that the approach being taken by Jun Tan and Paula Bickford to screen naturally occurring compounds as CD45 activators is one of the better ones, given that nutraceuticals generally tend to have fewer side effects and are better tolerated than designer drugs.
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