Activated microglia surrounding amyloid ␤-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 ␤ 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 ␤ to that of amylin, another amyloidotic peptide. Both lipopolysaccharide-treated THP-1 monocytes and mouse microglia showed significant increases in mature interleukin-1␤ release 48 h following amyloid ␤ or human amylin treatment, whereas nonfibrillar rat amylin had no effect on interleukin-1␤ production by THP-1 cells. Lipopolysaccharide-stimulated THP-1 cells treated with amyloid ␤ or amylin also showed increased release of the proinflammatory cytokines tumor necrosis factor-␣ and interleukin-6, as well as the chemokines interleukin-8 and macrophage inflammatory protein-1␣ and -1␤. THP-1 cells incubated with fibrillar amyloid ␤ or amylin in the absence of lipopolysaccharide also showed significant increases of both interleukin-1␤ and tumor necrosis factor-␣ 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.

No abstract

As noted in the introductory chapters of this book, neuritic plaques composed of accumulated amyloid β (Aβ) 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 Aβ1-42 isoform (7-11). Although it appears likely that the deposition of multimeric Aβ fibrils into plaques is a necessary step in AD onset, there is still uncertainty as to how Aβ and neuritic plaques might cause the neuropathology that leads to the dementia that is characteristic of this disease.