Inhibition of Colony-Stimulating Factor 1 Receptor by PLX3397 Prevents Amyloid Beta Pathology and Rescues Dopaminergic Signaling in Aging 5xFAD Mice

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. In this study, to investigate the effect of microglial elimination on AD progression, we administered PLX3397, a selective colony-stimulating factor 1 receptor inhibitor, to the mouse model of AD (5xFAD mice). Amyloid-beta (Aβ) deposition and amyloid precursor protein (APP), carboxyl-terminal fragment β, ionized calcium-binding adaptor molecule 1, synaptophysin, and postsynaptic density (PSD)-95 levels were evaluated in the cortex and hippocampus. In addition, the receptor density changes in dopamine D2 receptor (D2R) and metabotropic glutamate receptor 5 were evaluated using positron emission tomography (PET). D2R, tyrosine hydroxylase (TH), and dopamine transporter (DAT) levels were analyzed in the brains of Tg (5xFAD) mice using immunohistochemistry. PLX3397 administration significantly decreased Aβ deposition following microglial depletion in the cortex and hippocampus of Tg mice. In the neuro-PET studies, the binding values for D2R in the Tg mice were lower than those in the wild type mice; however, after PLX3397 treatment, the binding dramatically increased. PLX3397 administration also reversed the changes in synaptophysin and PSD-95 expression in the brain. Furthermore, the D2R and TH expression in the brains of Tg mice was significantly lower than that in the wild type; however, after PLX3397 administration, the D2R and TH levels were significantly higher than those in untreated Tg mice. Thus, our findings show that administering PLX3397 to aged 5xFAD mice could prevent amyloid pathology, concomitant with the rescue of dopaminergic signaling, suggesting that targeting microglia may serve as a useful therapeutic option for neurodegenerative diseases, including AD.

Plaque associated microglia hyper-secrete extracellular vesicles and accelerate tau propagation in a humanized APP mouse model

“…Microglia may play bidirectional roles for Aβ clearance via phagocytosis, endolysosomal clearance, and seeding of Aβ aggregates depending on the age of animals and the stage of Aβ accumulation in the brain. The general consensus of previous research regarding the effect of microglia depletion on amyloid deposition is that it is largely ineffectual aside from those utilizing the 5xFAD mouse model, which report dramatic improvements of Aβ pathology following microglia depletion [ 20 , 47 – 49 ]. Here we found that microglia depletion causes a sizeable increase in compact, but not diffuse amyloid deposition ( Supplemental Table S1 ).…”

Innate Immune System Activation and Neuroinflammation in Down Syndrome and Neurodegeneration: Therapeutic Targets or Partners?

“…Indeed, microglial reduction via CSF1R inhibition was found to rescue several cognitive deficits in Dp16 mice (Pinto et al, 2020 ). In AD mouse models, microglial depletion prior to amyloid deposition was shown to be critical for therapeutic efficacy (Sosna et al, 2018 ; Spangenberg et al, 2019 ; Son et al, 2020 ). Likewise, in mouse models of primary tauopathy, characterized by inclusions of the protein tau in neural cells (Kovacs, 2015 ), CSF1R inhibitors reduced pathological tau aggregation and subsequent neurodegeneration (Mancuso et al, 2019 ; Shi et al, 2019 ).…”

Interplay Between Microglia and Alzheimer’s Disease—Focus on the Most Relevant Risks: APOE Genotype, Sex and Age

“…The current clinical use of CSF1R inhibitors further confirms that short-term administration of CSF1R inhibitors can effectively eliminate human microglia (Butowski et al, 2016). Therefore, short-term elimination of microglia and cell proliferation may be a clinically feasible and novel method to solve neuroinflammatory events and promote brain recovery in brains affected by microglial dysfunction (Rice et al, 2017;Son et al, 2020). However, Since the recently obtained information on the different roles of microglia mainly comes from studies in mouse disease models, it is necessary for us to develop new disease models, including human induced pluripotent stem cells (iPSCs; Muffat et al, 2016;Bohlen et al, 2017;Gosselin et al, 2017), to fully understand which findings can be translated from mice to humans.…”