Abstract
Microglial cells closely interact with senile plaques in Alzheimer’s disease and acquire the morphological appearance of an activated phenotype. The significance of this microglial phenotype and the impact of microglia for disease progression have remained controversial. To uncover and characterize putative changes in the functionality of microglia during Alzheimer’s disease, we directly assessed microglial behavior in two mouse models of Alzheimer’s disease. Using in vivo two-photon microscopy and acute brain slice preparations, we found that important microglial functions - directed process motility and phagocytic activity - were strongly impaired in mice with Alzheimer’s disease-like pathology compared to age-matched non-transgenic animals. Notably, impairment of microglial function temporally and spatially correlated with Aβ plaque deposition, and phagocytic capacity of microglia could be restored by interventionally decreasing amyloid burden by Aβ vaccination. These data suggest that major microglial functions progressively decline in Alzheimer’s disease with the appearance of Aβ plaques, and that this functional impairment is reversible by lowering Aβ burden, e.g. by means of Aβ vaccination.
Highlights
Microglial cells execute important functions in the brain
We used thiscanonical function of microglia as a measure to evaluate their functionality in an Alzheimer’s disease (AD) mouse model in vivo by intravital time-lapse two-photon microscopy
The ability of microglia for directed extension of their processes towards a lesion was largely reduced in attracted to bamyloid (Ab) plaque carrying APPPS1-Cx3cr1+/gfp mice (Fig. 1A and B and Videos S1 and S2), which were obtained by crossbreeding APPPS1 mice, a mouse model of cerebral amyloidosis [21] with Cx3cr1gfp/gfp mice [23], a mouse model that allows visualization of microglia
Summary
Microglial cells execute important functions in the brain. They constantly survey their surrounding and react to acute tissue injuries [1,2]. Microglia are involved in shaping adult hippocampal neurogenesis through phagocytosis of apoptotic newborn neuroblasts [5] Together, these data highlight that socalled ‘‘resting’’ microglia in the healthy brain are able to modify their environment, e.g. by their intrinsic phagocytic activity [6]. In Alzheimer’s disease (AD), microglia are attracted to bamyloid (Ab) plaques, produce elevated levels of proinflammatory cytokines and reactive oxygen species, and exhibit a change in morphology [7,8,9,10,11]. These phenotypical and morphological changes of microglia are commonly interpreted as an ‘‘activated’’ state [12,13]. Microglial activation is not an all-or-none process and the morphology of microglial cells does not necessarily match their functional state [14,15]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
