Abstract
BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R.MethodsHere, we investigate the impact of such receptor on AD etiology and microglia. We deleted CSF1R using Cre/Lox system; the knockout (KO) is restricted to microglia in the APP/PS1 mouse model. We induced the knockout at 3 months old, before plaque formation, and evaluated both 6- and 8-month-old groups of mice.ResultsOur findings demonstrated that CSF1R KO did not impair microglial survival and proliferation at 6 and 8 months of age in APP cKO compared to their littermate-control groups APPSwe/PS1. We have also shown that cognitive decline is delayed in CSF1R-deleted mice. Ameliorations of AD etiology are associated with a decrease in plaque volume in the cortex and hippocampus area. A compensating system seems to take place following the knockout, since TREM2/β-Catenin and IL-34 expression are significantly increased. Such a compensatory mechanism may promote microglial survival and phagocytosis of Aβ in the brain.ConclusionsOur results provide new insights on the role of CSF1R in microglia and how it interacts with the TREM2/β-Catenin and IL-34 system to clear Aβ and ameliorates the physiopathology of AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world
colony-stimulating factor-1 receptor (CSF1R) is solely deleted in microglia CSF1R conditional knockout was made by a Cre/ Lox system (Fig. 1b)
We studied the expression of triggering receptor expressed on myeloid cells 2 (TREM2), β-Catenin, and IL-34 in young Wild type (WT) and conditional knockout (cKO) 10-week-old mice, because we postulated that these molecules can play an important role in AD by compensating for the KO
Summary
Microglia are the innate immune cells of CNS; their proliferation, activation, and survival in pathologic and healthy brain have previously been shown to be highly dependent on CSF1R. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the world. Beta-amyloid (Aβ) is the hallmark of AD. The cleavage of amyloid protein precursor (APP) by BACE1 and the enzymatic complex γ-secretase generates Aβ resulting in two main isoforms Aβ1–40. (Aβ40) and Aβ1–42 (Aβ42), the latter being the most toxic form [2]. Four to 6% of AD patients have genetic predisposition; early AD is associated with APP, PS1, and PS2 gene mutation, whereas late AD is related to a mutation of APOE 4 [3, 4]
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