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Chronic expression of inflammatory cytokines, including interleukin-1beta, tumor necrosis factor alpha, and interleukin-6, by glia may underlie the neurodegenerative events that occur within the brains of patients with Alzheimer's disease (AD). The present study determined whether these markers of inflammation could be observed within the brains of Tg(HuAPP695.K670N/M671L)2576 transgenic mice (Tg2576) that have recently been shown to mimic many features of AD. Interleukin-1beta- and tumor necrosis factor alpha-immunopositive microglia were localized with thioflavine-positive (fibrillar) Abeta deposits. Moreover, interleukin-6 immunoreactive astrocytes surrounded fibrillar Abeta deposits. These findings provide evidence that Tg2576 mice exhibit features of the inflammatory pathology seen in AD and suggest that these mice are a useful animal model for studying the role inflammation may play in this disease.

Increasing evidence points to A beta-containing senile plaques as primary etiological agents in Alzheimer's disease (AD). The mechanism by which these deposits cause neurotoxicity is unresolved, but there are compelling data suggesting that the activated glia found associated with senile plaques contribute to the pathology of AD. These cells appear to release a variety of immunoinflammatory molecules, including complement proteins whose activation products colocalize with senile plaques and dystrophic neurites. Previous studies showed that A beta can bind and activate complement protein C1q, providing a plausible explanation for the initiation of the complement cascade in AD. Data presented here further define the nature of A beta-C1q association, revealing key aspects of the C1q domain involved in binding the amyloid peptide. Moreover, we show that it is possible to inhibit A beta-induced complement activation without affecting the normal immunoglobulin-mediated complement pathway. This indicates that it should be feasible to develop drugs to reduce complement damage in AD without compromising this important immune-defense mechanism throughout the body.

Amyloid beta peptide (A beta), which is deposited as insoluble fibrils in senile plaques, is thought to play a role in the neuropathology of Alzheimer's disease. We have developed a model in which rat embryonic cerebral cortical or hippocampal neurons are seeded onto culture dishes containing deposits of substrate-bound, fibrillar A beta. The neurons attached rapidly to A beta 1-40 and A beta 1-42 substrates and extended long, branching neurites. Quantitative assessment demonstrated that survival of neurons on the A beta matrices was equivalent to or better than on control substrates of poly L-lysine or poly L-ornithine. In contrast, preparations of A beta fibrils added directly to the culture medium caused neuronal death as previously reported in the literature. These results reveal that the response of neurons to deposited A beta 1-40 and A beta 1-42 is substantially different from that observed with suspensions of the amyloid peptides, with the former serving as growth-promoting substrates for cortical and hippocampal neurons. This may thus imply that fibrillar A beta of senile plaques is not sufficient by itself to cause the plaque-associated neuronal degeneration characteristic of AD.

Because the mechanisms of A beta degradation in normal and Alzheimer's disease brain are poorly understood, we have examined whether various cortical cells are capable of processing this peptide. Rat microglia and astrocytes, as well as the human THP-1 monocyte cell line, degraded A beta 1-42 added to culture medium. In contrast, neither rat cortical neurons or meningeal fibroblasts effectively catabolized this peptide. When A beta fibrils were immobilized as plaque-like deposits on culture dishes, both microglia and THP-1 cells removed the peptide. Astrocytes were incapable of processing the A beta deposits, but these cells released glycosaminoglycase-sensitive molecules that inhibited the subsequent removal of A beta by microglia. This implied that astrocyte-derived proteoglycans associated with the amyloid peptide and slowed its degradation. The addition of purified proteoglycan to A beta that was in medium or focally deposited also resulted in significant inhibition of peptide removal by microglia. These data suggest that A beta can be catabolized by microglia and proteoglycans which co-localize with senile plaques may slow the degradation of A beta within these pathologic bodies.