Administration of CII in CFA produces features of RA including joint swelling, bone and cartilage degeneration, synovitis, and infiltration of inflammatory cells at the injection sites accompanied by sustained elevation of IL-1β and TNF-1β in plasma of wild-type and APP/PS1 mice. CIA reduces levels of Aβ and plaque burden in the cortex and hippocampus of APP/PS1 mice. The reduced amyloidosis is associated with BBB disruption and activation of microglia/macrophage. In contrast to the clearance of Aβ plaques, CIA enhances microcerebral pathology and mortality in APP/PS1 mice.
Inflammation can reduce amyloidosis and cognitive deficit in transgenic mouse models of AD. Amyloid plaque formation is enhanced in APP/PS1 mice overexpressing human COX-2, the inducible isoform of cyclooxygenase that is essential for prostaglandin E2 (PGE2)-mediated inflammation . Chronic administration of ibuprofen, a mixed COX-1/COX-2 inhibitor, prevents microglial activation, and reduces levels of inflammatory cytokines, Aβ, and amyloid plaque formation in Tg2576 mice [16, 17, 31]. The administration of COX-2 inhibitors prevents Aβ-mediated suppression of long-term plasticity and improves synaptic plasticity in Tg2576 . COX-2-mediated PGE2 production can enhance amyloidosis by reducing the phagocytic function of microglia and stimulating Aβ production through activation of the prostaglandin E2 and E4 receptors [32, 33].
Several lines of evidence suggest that inflammation negatively regulates amyloidosis and cognitive deficit in transgenic mouse models of AD. Overexpression of TGF-β1 or IL-6 reduces amyloid plaque formation through microglial activation in Tg2576 and TgCRND8 mice [34, 35]. Administration of G-CSF or M-CSF induces brain inflammation and ameliorates amyloid pathology and cognitive deficit in transgenic AD mice, including Tg 2576 [36, 37]. The intracerebral infection of Borna disease virus, which induces microglial cell activation, also reduces amyloid plaque formation in Tg2576 mice . Furthermore, overexpression of soluble complement receptor-related protein y, a complement inhibitor, reduces microglial activation, produces neurodegeneration, and enhances Aβ production and accumulation in human amyloid precursor protein transgenic mice bearing the amyloidogenic K670M, N671L, and V717F mutations .
Aβ produced in the brains of APP/PS1 mice or AD patients induces the expression and secretion of chemotactic cytokines, such as monocyte chemotactic protein 1, which enhances the transmigration and differentiation of monocytes from the bloodstream [40–42]. Circulating monocytes are increased in CIA-treated mice or RA patients, and are expected to transmigrate through the BBB into the brain areas exposed to Aβ. The brain monocytes can be differentiated into macrophages by cytokines such as M-CSF and IL-6, which are induced by Aβ or after CIA [35, 43–47]. Macrophages and activated microglia contribute to Aβ clearance. Alternatively, CIA may reduce the Aβ plaque burden by increasing passive transport to the periphery through increased BBB disruption.
Aβ accumulation in the cerebral vessel triggers BBB disruption by reducing the expression of tight junction proteins such as occludin, claudin-5, and zona occludins-1. Aβ can induce oxidative stress, mitochondrial dysfunction, and the activation of caspase-dependent apoptotic pathways, possibly through mechanisms involving interaction with RAGE, resulting in endothelial cell degeneration [48–50]. In the present study, we provide evidence that CIA-treated APP/PS1 mice develop vascular segments and atrophic string vessels characteristic of cerebrovascular pathology observed in AD patients.
Alzheimer's disease is occasionally accompanied by epileptic seizures . Cortical and hippocampal seizures are detected in three different APP transgenic mice models of AD . Seizures are frequently observed in APP/PS1 mice at 3 and 4.5 months of age and correlated with mortality that peaks at 3 to 4 months of age . In the present study, two APP/PS1 mice died at 3 to 4 months of age (6.7% mortality). In thirty nine APP/PS1 mice treated with CIA, nine mice died at 3 to 4 months of age (23.1% mortality). Thereafter, no death was observed. Thus, CIA may increase mortality of APP/PS1 mice by enhancing seizures, which is likely related with sustained inflammation and enhanced cerebrovascular pathology.
While further study is needed to delineate mechanisms underlying the effects of CIA on vascular pathology, elevated monocytes and neutrophils in CIA-treated APP/PS1 mice likely migrate to the cerebral vessel, release cytotoxic molecules such as superoxide, matrix metalloproteases, and TNF-α, and then contribute to endothelial cell degeneration and mortality in a cooperative way with Aβ. Recently, systemic administration of lipopolysaccharide for 6 weeks was shown to induce sustained microglial activation and tau hyperphosphorylation in the hippocampus of 3X Tg-AD mice harboring three mutant human genes (APPK670N;M671L, PS1M146V, and tauP301L) . Considering that lipopolysaccharide triggers systemic inflammation and BBB disruption, CIA may exacerbate tau pathology as well as vascular pathology in AD.