Determination of Spatial and Temporal Distribution of Microglia by 230nm-High-Resolution, High-Throughput Automated Analysis Reveals Different Amyloid Plaque Populations in an APP/PS1 Mouse Model of Alzheimers Disease

Katja      Scheffler; Jan      Stenzel; Markus      Krohn; Cathleen      Lange; Jacqueline      Hofrichter; Toni      Schumacher; Thomas      Bruning; Anne-Sophie      Plath; Lary      Walker; Jens      Pahnke

Abstract

One early and prominent pathologic feature of Alzheimers disease (AD) is the appearance of activated microglia in the vicinity of developing β-amyloid deposits. However, the precise role of microglia during the course of AD is still under discussion. Microglia have been reported to degrade and clear β-amyloid, but they also can exert deleterious effects due to overwhelming inflammatory reactions. Here, we demonstrate the occurrence of developing plaque populations with distinct amounts of associated microglia using time-dependent analyses of plaque morphology and the spatial distribution of microglia in an APP/PS1 mouse model. In addition to a population of larger plaques ( > 700μm2) that are occupied by a moderate contingent of microglial cells across the course of aging, a second type of small β-amyloid deposits develops (≤400μm2) in which the plaque core is enveloped by a relatively large number of microglia. Our analyses indicate that microglia are strongly activated early in the emergence of senile plaques, but that activation is diminished in the later stages of plaque evolution > 150 days). These findings support the view that microglia serve to restrict the growth of senile plaques, and do so in a way that minimizes local inflammatory damage to other components of the brain.

Keywords: Alzheimer's disease, AD, beta-amyloid, neurodegeneration, dementia, microglia, inflammation, immune therapy, blood-brain barrier, phagocytic mechanism, plaque growth, meningoencephalitis, diaminobenzidine