Protective microglial activation in Alzheimer’s disease pathogenesis

Abstract

Here it was of interest to determine the spatiotemporal relationships between Aβ, tau, and microglial pathological changes in post-mortem human AD brains by comparing differentially affected brain regions. Immunohistochemistry and fluorescence immunohistochemistry targeting Aβ, tau, and the pan-microglia marker ionised calcium binding adaptor molecule 1 (Iba1) was performed in four regions of decreasing pathological severity: inferior temporal cortex, superior frontal cortex, primary visual cortex, and primary motor cortex of ten controls, five controls with Alzheimer changes (CAc), and eight AD cases. Following a validated modified disector sampling approach, using manual and corroborative automated methods, the results showed that activated microglia predominated in the inferior temporal cortex of CAc. AD brains were characterised by increased clustering of activated microglia in the primary visual cortex and a substantial loss of clustering and ramified healthy microglia in the inferior temporal cortex. Activated microglia were found to internalise Aβ pathology but not tau pathology. Further, microglia were found to phagocytose greater quantities of pre-synapses in AD compared to both CAc and controls in a study using super-resolution microscopy. Gene amplification studies of a number of candidate genes were performed in coronal neonatal mouse brain slice cultures treated with synthetic preparations of Aβ. Findings demonstrated the upregulation of select phagocytic and anti-inflammatory markers in response to low-dose Aβ monomers. Additionally, a validation amplification study confirmed findings from an RNA-Seq study which demonstrated the upregulation of gene transcripts related to immune pathways and phagocytosis in mildly affected regions of the AD brain. Taken together, these findings are indicative of neuroprotective activation of microglia early in the pathogenesis of AD