To further elucidate the WNV-S100B neurotoxic pathway, in vivo studies using mouse models are warranted.
In this neurotoxic pathway, A β triggers calcium influx, which activates calpain activity and subsequent cleavage of p35 to p25, a stable activator of CDK5 that promotes the hyperphosphorylation of downstream substrates of CDK5.
Therefore, overproduction of TNF- α is strongly linked with neuronal damage, and blockage of TNF- α-mediated neurotoxic pathway emerges as an attractive strategy for the treatment of degenerative diseases such as AD and PD.
Elevated S100B level has been shown to be involved in neurotoxic pathways (Mrak et al., 1996; Rothermundt et al., 2003).
Similar to microglia, these cells may induce beneficial effects, but also contribute to neurodegeneration through uncontrolled inflammation and/or neurotoxic pathways.
Results such as these might be further improved when multiple proteins, such as Aβ and tau, and multiple neurotoxic pathways are concurrently targeted.
Recently, both Bax-dependent and Bax-independent neurotoxic pathways were found in mice with N-terminally deleted forms of the prion protein (Li et al., 2007).
Together, these studies indicate that microglia and monocyte-derived cells also play an important role in promoting proinflammatory and neurotoxic pathways.
Thus, finding a way to promote effective Aβ clearance in these cells, while avoiding the activation of proinflammatory and neurotoxic pathways, should prove an attractive target for AD therapies.
Although it is tempting to link AD development to Aβ-induced attenuation of DNA-PK activity and hence to reduced NHEJ activity, it may be argued that this event is a consequence rather than the prime cause, a simultaneous event that could occur independently of Aβ-triggered neurotoxic pathways.
In a recent study by Mizwicki and colleagues, the authors treated peripheral blood mononuclear cells from AD patients with 1α,25-dihydroxyvitamin D3 (1,25D3), the active metabolite of vitamin D, and resolvin D1 (RvD1), a derivative of omega-3 fatty acids, in an effort to balance the activation of inflammation, specifically avoiding neurotoxic pathways and promoting effective Aβ phagocytosis.
