Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition

Abstract

BackgroundPro-inflammatory stimuli, including cytokines like Interleukin-1β, Interleukin-6 and Interferon-γ, in the brain have been proposed to exacerbate existing Alzheimer’s disease (AD) neuropathology by increasing amyloidogenic processing of APP and promoting further Aβ accumulation in AD. On the other hand, anti-inflammatory cytokines have been suggested to be neuroprotective by reducing neuroinflammation and clearing Aβ. To test this hypothesis, we used adeno-associated virus serotype 1 (AAV2/1) to express an anti-inflammatory cytokine, murine Interleukin-4 (mIL-4), in the hippocampus of APP transgenic TgCRND8 mice with pre-existing plaques.ResultsmIL-4 expression resulted in establishment of an “M2-like” phenotype in the brain and was accompanied by exacerbated Aβ deposition in TgCRND8 mice brains. No change in holo APP or APP C terminal fragment or phosphorylated tau levels were detected in mIL-4 expressing CRND8 cohorts. Biochemical analysis shows increases in both SDS soluble and insoluble Aβ. mIL-4 treatment attenuates soluble Aβ40 uptake by microglia but does not affect aggregated Aβ42 internalization by microglia or soluble Aβ40 internalization by astrocytes.ConclusionsShort term focal mIL-4 expression in the hippocampus leads to exacerbation of amyloid deposition in vivo, possibly mediated by acute suppression of glial clearance mechanisms. Given that recent preclinical data from independent groups indicate engagement of the innate immune system early on during disease pathogenesis may be beneficial, our present study strongly argues for a cautious re-examination of unwarranted side–effects of anti-inflammatory therapies for neurodegenerative diseases, including AD.

Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes

“…There is a large amount of evidence to show that increased proinflammatory cytokines correlates with Aβ production and neurodegeneration. In contrast, there are also a number of studies indicating that proinflammatory cytokines precondition the system for Aβ challenge and protect against neurodegeneration (82)(83)(84)(85). Clearly, inflammation is a major component of the AD brain, and more work will be required in order to elucidate its role in AD pathogenesis.…”

Silibinin rescues learning and memory deficits by attenuating microglia activation and preventing neuroinflammatory reactions in SAMP8 mice

“…On the other hand, the relationship of IL-4 to AD pathology is very complex. It has been reported that overexpression of IL-4 in TgCRND8 mice increased Aβ deposition [25]. IL-4 has also been shown to increase the clearance of oligomeric Aβ by microglia in vitro and decrease Aβ deposition in APP/PS1 transgenic mice [26,27].…”

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

“…Though these types of 'conversion studies' are associated with severe inherent limitations, they substantiate the potential diagnostic relevance of neuroinflammatory cytokine alterations in AD [185]. Despite the proposed and increasingly established roles of proinflammatory cytokine alterations in disease pathogenesis in AD, controversial results have also been published demonstrating deleterious effects of anti-inflammatory cytokines and beneficial effects of proinflammatory cytokines in terms of brain Aβ clearance in vivo [186][187][188][189][190]. Of note, generally disappointing results have been obtained from studies aiming at the modification of inflammatory response in AD with nonsteroidal anti-inflammatory drugs (NSAIDs) or elective cyclooxygenase-2 (COX-2) inhibitors at the clinical level [191][192][193][194][195].…”