Sundaram JR, Chan ES, Poore CP, Pareek TK, Cheong WF, Shui G, Tang N, Low CM, Wenk MR, Kesavapany S.
Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration.
J Neurosci. 2012 Jan 18;32(3):1020-34.
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The role of inflammation in neurodegeneration has been a hotly debated topic for the past three decades, at least. Two of the key issues regard whether neuroinflammation is 1) an early event and 2) a prime mover in the pathobiology of neurodegenerative diseases including AD. While considerable pathomechanistic focus has been given to cytokines and chemokines, much less attention has been paid to lipid mediators of inflammation. At some level, this is counterintuitive, because phospholipase A2 metabolism of the essential fatty acid arachidonic acid, leading to production of eicosanoids, is pathognomonic of classical inflammation.
This report by Sundaram et al. describes the consequences of driving p25/Cdk5 activity on neuroinflammation and neuronal death both in vivo and in vitro. Previous studies, chiefly from Li Huei-Tsai’s group, established that activation of Cdk5 via proteolytic cleavage of p35 to p25 is a key event in AD patients’ brains and promotes neurodegeneration. However, the role of brain inflammation in this process has not been elucidated. The Kesavapany group now convincingly demonstrates that the Cdk5/p25 pathway triggers neuroinflammation via lysophosphatidylcholine (LPC) that precedes and leads to neurodegeneration and neuronal loss (in vitro). These findings are highly important, as they provide direct evidence of 1 and 2 above—that neuroinflammation, at least as initiated by Cdk5/p25 activation, occurs early and predisposes to neurodegenerative changes.
One other aspect of this report that I would like to highlight is the relationship between Cdk5/p25 inflammation and Aβ pathology. Interestingly, the authors showed that early neuroinflammation triggered by inducible Cdk5/p25 expression in vivo later led to copious intraneuronal Aβ. One interpretation of this finding, supported by others in the field, is that Aβ production signifies an acute-phase stress response that can both be initiated by neuroinflammation and drive it. If this is indeed the case, then one could imagine a viscous feed-forward loop endorsing a constellation of damaging inflammatory mediators. Perhaps this may explain why intracranial administration of LPC alone was not sufficient to induce neuronal death in vivo in the authors’ hands. Nonetheless, these findings are highly important to the field of neuroinflammation as related to neurodegenerative diseases.
Lysophosphatidylcholine (LPC) is one of the plasma lipids and can be generated by the action of cytosolic phospholipase A2 (cPLA2). Because of its proinflammatory functions, the levels of LPC must be tightly controlled by lysophospholipase or LPC-acyltransferase. In this recent study examining the role of Cdk5/p25 in neuroinflammation, Kesavapany and colleagues make the compelling observation that p25 overexpression leads to increased release of LPC through the activation of cPLA2. The cleavage of p35 to p25 has been implicated in AD, since it can promote phosphorylation of tau and neuronal death. Most interestingly, they demonstrate that LPC-mediated neuroinflammation events occur prior to signs of neurodegeneration in cultures overexpressing p25 and in vivo in p25 transgenic mice. Reduction of cPLA2 lowered the expression of p25-mediated inflammatory cytokines. Taken together, these results suggest a complex relationship between neuroinflammation and neurodegeneration, and, importantly, highlight a novel role for soluble lipid factors in Cdk5/p25-mediated astrogliosis.
Of particular note, the commentary by Terrence Town nicely illustrated the current status of the AD field regarding the proposed feed-forward mechanism of Aβ in neuroinflammation. Another key question raised by the study is how p25-mediated upregulation of cytokine production ultimately leads to cell death. The relationship between astrocytes and neurons overexpressing p25 is complicated by the involvement of microglia, as their role in neurodegeneration is still poorly understood. It will thus be intriguing to examine these aspects in addition to Cdk5/p25-mediated contributions to reactive oxygen species, regulation of cytokine levels and activity, and peripheral cell recruitment. Finally, it will be critical to assess precisely how Cdk5/p25-mediated neuroinflammation affects downstream events such as tau phosphorylation and Aβ accumulation in order to better understand the precise mechanisms underlying the pathophysiology of AD.
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