Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review

Abstract

Neuroinflammation is proposed as one of the mechanisms by which Alzheimer’s disease pathology, including amyloid-β plaques, leads to neuronal death and dysfunction. Increases in the expression of markers of microglia, the main neuroinmmune cell, are widely reported in brains from patients with Alzheimer’s disease, but the literature has not yet been systematically reviewed to determine whether this is a consistent pathological feature. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to 23 February 2017. Papers were included if they quantitatively compared microglia markers in post-mortem brain samples from patients with Alzheimer’s disease and aged controls without neurological disease. A total of 113 relevant articles were identified. Consistent increases in markers related to activation, such as major histocompatibility complex II (36/43 studies) and cluster of differentiation 68 (17/21 studies), were identified relative to nonneurological aged controls, whereas other common markers that stain both resting and activated microglia, such as ionized calcium-binding adaptor molecule 1 (10/20 studies) and cluster of differentiation 11b (2/5 studies), were not consistently elevated. Studies of ionized calcium-binding adaptor molecule 1 that used cell counts almost uniformly identified no difference relative to control, indicating that increases in activation occurred without an expansion of the total number of microglia. White matter and cerebellum appeared to be more resistant to these increases than other brain regions. Nine studies were identified that included high pathology controls, patients who remained free of dementia despite Alzheimer’s disease pathology. The majority (5/9) of these studies reported higher levels of microglial markers in Alzheimer’s disease relative to controls, suggesting that these increases are not solely a consequence of Alzheimer’s disease pathology. These results show that increased markers of microglia are a consistent feature of Alzheimer’s disease, though this seems to be driven primarily by increases in activation-associated markers, as opposed to markers of all microglia.

The relationship between the morphological subtypes of microglia and Alzheimer’s disease neuropathology

“…Although IBA1 is recognized as an effective pan‐microglial marker , more subtle changes in activation including phagocytic status may have been missed. For example, other human post‐mortem studies have demonstrated upregulation of major histocompatibility complex class II (MHC II) and cluster of differentiation 68 (CD68), markers of activation and phagocytosis, respectively; see review .…”

Microglia and the aging brain: are senescent microglia the key to neurodegeneration?

“…However, there has been recent discussion as to whether these microglia are activated or dystrophic and which form is mostly likely to be causative in the relevant pathological changes (Navarro et al ). Even considering a possible activated state, evidence suggest that both markers of M1 and M2 activation states are present in AD (Hopperton et al ). Other studies suggest both activation states are present at different times (Tang and Le ).…”

“…Single‐cell RNA‐sequencing studies also suggest that there is continuous, heterogeneous spectrum of states present in the brains of mouse models of AD (von Maydell and Jorfi ). A comparison of microglial markers between individuals with AD and high‐pathology but cognitively normal controls showed that microglial activation is increased in AD, suggesting that microglial activation is not simply a reaction to AD pathology such as β‐amyloid deposition (Hopperton et al ). It is possible that microglia are pushed towards a more pro‐inflammatory phenotype through age‐related changes.…”

“…A systematic review of microglial markers in AD found that most studies observed increases in markers related to microglial activation, but no significant difference in overall microglial markers. They also found no difference in overall cell counts suggesting that microglial number does not increase in AD, but microglial levels of activation do (Hopperton et al ).…”

Neuroimmune nexus of depression and dementia: Shared mechanisms and therapeutic targets

“…Consistent with this, microglia activation patterns are region specific in both AD and MDD. While a range of markers associated with microglia activation (CD68, MHCII, ionized calcium‐binding adapter molecule 1, , and CD11c) are broadly overexpressed in the frontal, orbitofrontal, cingulate, and temporal cortices of biopsied AD brains (Hopperton, Mohammad, Trépanier, Giuliano, & Bazinet, ), their activation pattern (IL‐1 receptor) in the parahippocampal cortex has laminar specificity, particularly in layers III–IV (Sheng, Griffin, Royston, & Mrak, ). Characterization of microglia activation in AD patients using PET imaging with 18 FEPPA binding to mitochondrial also supports the presence of inflammatory or phagocytic microglia in the anterior cingulate cortex (ACC), temporal cortices, multiple frontal gyri, and striatal regions (Edison et al, ).…”