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.
Highlights
Aging of the global population has led to a rapid increase in the incidence of Alzheimer’s disease (AD), and there is a growing need for an effective therapeutic drug for AD in order to improve the quality of life of AD patients during old age
To investigate the effect of PLX3397 on a mouse model of AD, 5xFAD mice at the age of 9 months were treated with PLX3397 by daily oral gavage to the mice at 50 mg·kg−1 for 30 days (Figure 1)
Oral PLX3397 administration led to a decrease in Aβ deposition in the cortex of the mice
Summary
Aging of the global population has led to a rapid increase in the incidence of Alzheimer’s disease (AD), and there is a growing need for an effective therapeutic drug for AD in order to improve the quality of life of AD patients during old age. There is still a lack of clinical diagnostic parameters for living patients; postmortem neuropathologic evaluation has shown that the histopathology of AD is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, neuron and synapse loss, and dystrophic neurites [1]. Histopathological studies have shown that activated microglial cells surround amyloid plaques [6,7,8]. A few studies reported that depleting microglia with a colony-stimulating factor 1 receptor (CSF1R) inhibitor during the disease process prevented amyloid plaque accumulation in the brains of AD animal models at an early stage of the disease [11,12]. PLX3397 is already in a Phase 3 clinical study for pigmented villonodular synovitis [14]; its therapeutic effects on the late stage of AD have not yet been investigated. In this study, we examined the impact of PLX3397 treatment during the late stage of the disease, which involves severe Aβ pathology, by using the 5xFAD mouse model, an AD mouse model
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
