Is There Any Evidence of Monocytes Involvement in Alzheimer’s Disease? A Pilot Study on Human Postmortem Brain

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.

Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer’s disease hippocampus

“…This conflict is generated by the absence of “exclusive” molecular markers that allow a clear distinction between microglia and circulating monocytes. In fact, previous reports, using AD models or human post-mortem samples, described both the presence and/or the absence of peripheral infiltration into the cerebral parenchyma [ 22 , 33 , 40 ]. In this work, we have reevaluated this problem by combining molecular and quantitative morphological approaches in hippocampal samples from AD patients.…”

Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer’s Disease

“…Intermediate monocytes are expertise at antigen presentation, cytokine secretion, apoptosis regulation, and transendothelial migration [ 23 ]. The infiltration of intermediate monocytes into the CNS due to leaky BBB remains debatable and our findings provide indirect evidence of infiltrative intermediate monocytes into the brain [ 24 ]. Furthermore, we also studied HLA-DR + monocytes to investigate adaptive immunity in AD progression.…”

Genetic insights into immune mechanisms of Alzheimer’s and Parkinson’s disease

“…Spatially, alterations in cell state have been observed in microglia near amyloid plaques and microglia in the white matter prior to amyloid deposition ( 62 , 63 ). Additional myeloid cell types that may also play a role in AD pathogenesis include infiltrating monocytes ( 64 ), choroid plexus macrophages ( 65 ), perivascular macrophages ( 66 , 67 ) and border-associated macrophages ( 68 ). The immune contribution of common genetic variants for brain disorders has largely focused on microglia because they are the predominant brain resident macrophage.…”