Regular Articles
Association of Microglia with Amyloid Plaques in Brains of APP23 Transgenic Mice

https://doi.org/10.1016/S0002-9440(10)65423-5Get rights and content

Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD, the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between β-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-β precursor protein (βPP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14- to 18- month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1- and phosphotyrosine-positive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice, early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally, bundles of amyloid fibrils, sometimes surrounded by an incomplete membrane, were observed within the microglial cytoplasm. However, microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal, contributory, or consequential to cerebral amyloidosis, our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived βPP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived βPP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice.

Cited by (0)

Supported by grants 3130–44526.95 and 3100–46612.96 from the Swiss National Foundation.

View Abstract