Microglia Demonstrate Local Mixed Inflammation and a Defined Morphological Shift in an APP/PS1 Mouse Model

Abstract

Background: Microglia are traditionally described as the immune cells of the brain and have an inflammatory role in Alzheimer’s disease (AD). Microglial morphological and phenotypic shifts in AD have not been fully characterized; however, microglia are often described as either pro- or anti-inflammatory. Objective: To determine microglial if microglial morphology and phenotype changes with disease status. Methods: This study observed morphology through Iba1 immunohistochemistry on tissue sections encompassing the primary motor cortex and somatosensory barrel fields. Immunohistochemistry for pro-inflammatory markers: CD14 and CD40; and anti-inflammatory markers: CD16 and TREM2, was performed at 3, 6, and 12 months of age which correlated with pre-plaque, onset, and significant plaque load in APP/PS1 brains (n = 6) and compared to age-matched littermate controls (n = 6). Results: Microglia demonstrated a defined morphological shift with time. Deramified morphologies increased in the APP/PS1, at both 6 months (p < 0.0001) and 12 months (p < 0.0001). At 12 months, there were significantly lower numbers of ramified microglia (p < 0.001). Results indicated that microglia have a heterogenic marker immunoreactivity as CD16, TREM2, and CD40 were associated with an activated morphology at the same time points. All inflammatory markers were significantly upregulated at 12 months in the APP/PS1 mice (TREM2 (F (2,30) = 10.75, p = 0.0003), CD40 (F (2,30) = 15.86, p < 0.0001), CD14 (F (2,30) = 6.84, p = 0.0036), and CD16 (F (2,30) = 3.026, p = 0.0635)). Conclusion: Our data indicate that pro- and anti-inflammatory factors of microglia occur in APP/PS1 mice.

Functional and Phenotypic Diversity of Microglia: Implication for Microglia-Based Therapies for Alzheimer’s Disease

“…Interestingly, bipolar/rod-shaped microglia in various subcortical regions of AD brains displayed high immunoreactivity against tau protein, suggesting that they might be involved in the internalization of NFTs or degenerating neurons with high loads of hyperphosphorylated tau ( Odawara et al, 1995 ). Similarly, bipolar/rod-shaped microglia were also found in aged chimpanzees with AD-like pathology ( Edler et al, 2018 ), and APP/PS-1 mouse model of AD ( Holloway et al, 2020 ). Interestingly, a recent study demonstrated that the occurrence of bipolar/rod-shaped microglia in cerebral cortex and hippocampus increased with age.…”

“…Over the past decades, much effort has been attributed to characterize ramified (resting) and amoeboid (activated) microglia in various neurological disorders that might be an oversimplification. Apart from the classical subdivision of microglia into ramified and amoeboid microglia, bipolar/rod-shaped microglia also appeared in the brains under several pathological conditions ( Ziebell et al, 2012 ; Taylor et al, 2014 ; Au and Ma, 2017 , 2022 ; Bachstetter et al, 2017 ; Edler et al, 2018 ; Holloway et al, 2020 ). In fact, bipolar/rod-shaped microglia was the first form of activated microglia characterized by Nissl in 1899 ( Nissl, 1899 ).…”