Abstract
BACKGROUND: The role of neuroinflammation has become more evident in the pathogenesis of neurodegenerative diseases. Increased expression of microglial markers is widely reported in Alzheimer's disease (AD), but much less is known about the role of monocytes in AD pathogenesis. In AD animal models, bone marrow-derived monocytes appear to infiltrate the parenchyma and contribute to the phagocytosis of amyloid-β depositions, but this infiltration has not been established in systematic studies of the human brain postmortem. OBJECTIVE: In addition to assessing the distribution of different subtypes of microglia by immunostaining for CD68, HLA-DR, CD163, and CD206, we focused on the involvement of C-chemokine receptor type2 (CCR2) positive monocytes during the AD course. METHODS: We used formalin-fixed and paraffin-embedded tissue from four vulnerable brain regions (hippocampus, occipital lobe, brainstem, and cerebellum) from neuropathologically characterized AD cases at different Braak stages and age-matched controls. RESULTS: Only singular migrated CCR2-positive cells were found in all brain regions and stages. The brainstem showed the highest number of positive cells overall, followed by the hippocampus. This mechanism of recruitment seems to work less efficiently in the human brain at an advanced age, and the ingress of monocytes obviously takes place in much reduced numbers or not at all. CONCLUSION: In contrast to studies on animal models, we observed only a quite low level of myeloid monocytes associated with AD pathology. Furthermore, we provide evidence associating early microglial reactions carried out in particular by pro-inflammatory cells with early effects on tangle- and plaque-positive vulnerable brain regions.