Multiple inflammatory profiles of microglia and altered neuroimages in APP/PS1 transgenic AD mice

Jan 14, 2020Brain research bulletin

Different inflammation patterns in brain immune cells and brain changes in Alzheimer's model mice

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Abstract

Microglia were activated around Aβ plaques in TgAPP/PS1 mice as early as 6 months, indicating potential early biomarkers for Alzheimer's disease.

Aβ plaques in Alzheimer's disease may precede cognitive deficits by decades, but early diagnostic biomarkers are currently unavailable.
Microglia and astrocytes showed activation and clustering around Aβ plaques, with microglial activation increasing significantly between 6 and 12 months.
Phagocytosis of Aβ was observed in microglia but not in astrocytes at 6 months of age.
Activated microglia upregulated proinflammatory and anti-inflammatory factors, while reactive astrocytes did not express these cytokines.
A decrease in neural stem cells and immature neurons was noted in 3-month-old TgAPP/PS1 mice prior to Aβ deposits.
Diffusion tensor imaging indicated reduced fractional anisotropy in the dentate gyrus and altered connectivity in brain networks at 6 months.

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Aβ plaques of Alzheimer's disease (AD) are believed to precede cognitive deficits or clinical manifestation by decades. However, validated biomarkers for early diagnosis of the AD disease are still not available. In this present study, we combined MRI-based neuroimages and histological assessment of the glial response and altered cytokines, neurogenesis during the early course of Aβ deposits in TgAPP/PS1 mice to find potential early biomarkers for AD. We found that microglia and astrocytes were initially activated and clustered around Aβ plaques at the age of 6 months and significantly increased with age from 6-12 months of age. Confocal microscope analysis revealed that microglia not astrocytes began to phagocytose Aβ in 6-month-old TgAPP/PS1 mice, evidenced by the intracellular Aβ in Iba1 positive microglia not in GFAP positive astrocytes. In parallel with these observations, we found that mainly clustered microglia significantly upregulated the production of proinflammatory factors including TNF-α, iNOS and IL-1β, and anti-inflammatory cytokines including IL-4, TGF-β and extracellular protecting matrix YM-1 and enzyme arginase 1 (Arg1) at 6-12 months of age. Interestingly, reactive astrocyte did not express these cytokines and YM-1 and Arg1. These results may suggest that microglia rather than astrocytes play crucial roles in clearing Aβ and neuroinflammation in early stage of AD. In addition, the number of neural stem cells labeled by BrdU and immature neurons labeled by doublecortin was significantly decreased in 3-month-old TgAPP/PS1 mice ahead of Aβ deposits. Finally, DTI conforms that reduced fractional anisotropy (FA) in dentate gyrus of hippocampus and rs-MRI shows an increased connectivity in the networks of somatosensory cortex-caudoputamen and insula in TgAPP/PS1 mice at 6 months. These findings provide a clue to early biomarkers for diagnosis of the AD disease.

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Multiple inflammatory profiles of microglia and altered neuroimages in APP/PS1 transgenic AD mice

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