Amyloid beta and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia.

Activated microglia surrounding amyloid beta-containing senile plaques synthesize interleukin-1, an inflammatory cytokine that has been postulated to contribute to Alzheimer's disease pathology. Studies have demonstrated that amyloid beta treatment causes increased cytokine release in microglia and related cell cultures. The present work evaluates the specificity of this cellular response by comparing the effects of amyloid beta to that of amylin, another amyloidotic peptide. Both lipopolysaccharide-treated THP-1 monocytes and mouse microglia showed significant increases in mature interleukin-1beta release 48 h following amyloid beta or human amylin treatment, whereas nonfibrillar rat amylin had no effect on interleukin-1beta production by THP-1 cells. Lipopolysaccharide-stimulated THP-1 cells treated with amyloid beta or amylin also showed increased release of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6, as well as the chemokines interleukin-8 and macrophage inflammatory protein-1alpha and -1beta. THP-1 cells incubated with fibrillar amyloid beta or amylin in the absence of lipopolysaccharide also showed significant increases of both interleukin-1beta and tumor necrosis factor-alpha mRNA. Furthermore, treatment of THP-1 cells with amyloid fibrils resulted in an elevated expression of the immediate-early genes c-fos and junB. These studies provide further evidence that fibrillar amyloid peptides can induce signal transduction pathways that initiate an inflammatory response that is likely to contribute to Alzheimer's disease pathology.

Aß-Induced Proinflammatory Cytokine Release from Differentiated Human THP-1 Monocytes.

As noted in the introductory chapters of this book, neuritic plaques composed of accumulated amyloid ß (Aß) peptide are a hallmark pathological feature of the Alzheimer's disease (AD) brain. Compelling genetic data now implicate these plaques as key causative agents in AD onset, as all known mutations that lead to early onset familial AD (1-6) result in an increased production of the amyloidogenic Aß1-42 isoform (7-11). Although it appears likely that the deposition of multimeric Aß fibrils into plaques is a necessary step in AD onset, there is still uncertainty as to how Aß and neuritic plaques might cause the neuropathology that leads to the dementia that is characteristic of this disease.

Inflammatory responses to amyloid fibrils.

Our laboratory has routinely used the methodologies described here to characterize the effects of fibrillar A beta and amylin on cytokine synthesis and secretion by LPS-differentiated THP-1 cells. Because LPS-treated THP-1 cells resemble macrophage and microglia, this assay system represents an in vitro model of the potential interactions between A beta-containing senile plaques and microglia in the AD brain. As such, these methodologies should prove useful in the identification of compounds that inhibit this A beta-induced inflammatory response.