Microglia senescence occurs in both substantia nigra and ventral tegmental area

Abstract

During aging humans lose midbrain dopamine neurons, but not all dopamine regions exhibit vulnerability to neurodegeneration. Microglia maintain tissue homeostasis and neuronal support, but microglia become senescent and likely lose some of their functional abilities. Since aging is the greatest risk factor for Parkinson's disease, we hypothesized that aging‐related changes in microglia and neurons occur in the vulnerable substantia nigra pars compacta (SNc) but not the ventral tegmental area (VTA). We conducted stereological analyses to enumerate microglia and dopaminergic neurons in the SNc and VTA of 1‐, 6‐, 9‐, 18‐, and 24‐month‐old C57BL/J6 mice using sections double‐stained with tyrosine hydroxylase (TH) and Iba1. Both brain regions show an increase in microglia with aging, whereas numbers of TH+ cells show no significant change after 9 months of age in SNc and 6 months in VTA. Morphometric analyses reveal reduced microglial complexity and projection area while cell body size increases with aging. Contact sites between microglia and dopaminergic neurons in both regions increase with aging, suggesting increased microglial support/surveillance of dopamine neurons. To assess neurotrophin expression in dopaminergic neurons, BDNF and TH mRNA were quantified. Results show that the ratio of BDNF to TH decreases in the SNc, but not the VTA. Gait analysis indicates subtle, aging‐dependent changes in gait indices. In conclusion, increases in microglial cell number, ratio of microglia to dopamine neurons, and contact sites suggest that innate biological mechanisms compensate for the aging‐dependent decline in microglia morphological complexity (senescence) to ensure continued neuronal support in the SNc and VTA.

Partial microglial depletion is associated with impaired hippocampal synaptic and cognitive function in young and aged rats

“…Consistent with the literature, we observed age‐related differences in microglia associated with increased microglial activation. For control animals, we confirmed an age‐related increase in Iba‐1 expression in the hippocampus, increased number of CA1 microglial cells, and a slight reduction in microglial branch length, consistent with microglial activation (Chan et al, 2018; Damani et al, 2011; Hefendehl et al, 2014; Perkins, Piazza, & Deak, 2018; Shaerzadeh et al, 2020; Tremblay, Zettel, Ison, Allen, & Majewska, 2012). Similarly, we confirmed an age‐related decrease in CA1 synaptic transmission (Barnes, Rao, & Shen, 1997; Billard & Rouaud, 2007; Bodhinathan et al, 2010; Kumar & Foster, 2013), which may be linked to microglial activation (Barter et al, 2020; Kim et al, 2018).…”

“…No additional morphological measures significantly varied between the groups. In conclusion, microglia exhibited a strong impact of aging, with greater microglial activation indicated as more microglia and shorter branches (Hopperton, Mohammad, Trépanier, Giuliano, & Bazinet, 2018; Shaerzadeh et al, 2020; Streit et al, 2004; Streit & Xue, 2013). PLX3397‐treated young and aged animals exhibited microglial depletion, and aged depleted rats had the fewest microglia along with shorter branches.…”

Microglia drive pockets of neuroinflammation in middle age

“…We did not detect substantial neuron loss in the VTA/SNc by 18mo of age ( Fig. 7 ), in agreement with other reports 62,63 , suggesting that early increases in microglial abundance are unlikely to be caused by neuronal death in these brain regions. Although systemic inflammation can promote microglial proliferation 64 , we did not detect increases in plasma levels of inflammation until 24mo of age, well after increased VTA/SNc microglial proliferation.…”

“…S1 ). Several studies have reported no change in substantia nigra 33 , progressive decreases in substantia nigra 61 , or transient decreases in VTA and SNc microglial number during aging 62 . These studies generally rely on Iba1 immunostaining, which may be more difficult to accurately quantify than genetically-encoded fluorescent markers.…”

Microglia become hypofunctional and release metalloproteases and tau seeds after phagocytosing live neurons with P301S tau aggregates

“…The molecular differences between the different states of the microglia under these different settings remain to be resolved.In addition to microglia being hypophagocytic, we show that coculture of microglia with P301S tau aggregate-containing neurons induced the hypofunctional microglia to secrete several senescence-associated factors (CXCL1, CXCL2, CCL5, IGFBP3, MMP9, and MMP3 (62)). The presence of dystrophic microglia that have been linked to senescence have been reported in Alzheimer's disease and other neurodegenerative disorders(63)(64)(65)(66) although no molecular signatures of senescence were recorded. Loss of phagocytic capacity, increased SA-β-gal activity, and altered cytokine profiles such as those we describe here are common signs of senescence.…”