Glial activation and inflammation along the Alzheimer’s disease continuum

Abstract

Background Neuronal and glial cell interaction is essential for synaptic homeostasis and may be affected in Alzheimer’s disease (AD). We measured cerebrospinal fluid (CSF) neuronal and glia markers along the AD continuum, to reveal putative protective or harmful stage-dependent patterns of activation. Methods We included healthy controls ( n = 36) and Aβ-positive (Aβ+) cases (as defined by pathological CSF amyloid beta 1-42 (Aβ42)) with either subjective cognitive decline (SCD, n = 19), mild cognitive impairment (MCI, n = 39), or AD dementia ( n = 27). The following CSF markers were measured: a microglial activation marker—soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of microglial inflammatory reaction—monocyte chemoattractant protein-1 (MCP-1), two astroglial activation markers—chitinase-3-like protein 1 (YKL-40) and clusterin, a neuron-microglia communication marker—fractalkine, and the CSF AD biomarkers (Aβ42, phosphorylated tau (P-tau), total tau (T-tau)). Using ANOVA with planned comparisons, or Kruskal-Wallis tests with Dunn’s pairwise comparisons, CSF levels were compared between clinical groups and between stages of biomarker severity using CSF biomarkers for classification based on amyloid pathology (A), tau pathology (T), and neurodegeneration (N) giving rise to the A/T/N score. Results Compared to healthy controls, sTREM2 was increased in SCD ( p < .01), MCI ( p < .05), and AD dementia cases ( p < .001) and increased in AD dementia compared to MCI cases ( p < .05). MCP-1 was increased in MCI ( p < .05) and AD dementia compared to both healthy controls ( p < .001) and SCD cases ( p < .01). YKL-40 was increased in dementia compared to healthy controls ( p < .01) and MCI ( p < .05). All of the CSF activation markers were increased in subjects with pathological CSF T-tau (A+T−N+ and A+T+N+), compared to subjects without neurodegeneration (A−T−N− and A+T−N−). Discussion Microglial activation as indicated by increased sTREM2 is present already at the preclinical SCD stage; increased MCP-1 and astroglial activation markers (YKL-40 and clusterin) were noted only at the MCI and AD dementia stages, respectively, and in Aβ+ cases (A+) with pathological T-tau (N+). Possible different effects of early and later glial activation need to be explored. Electronic supplementary material The online version of this article (10.1186/s12974-019-1399-2) contains supplementary material, which is available to authorized users.

New fluid biomarkers tracking non-amyloid-β and non-tau pathology in Alzheimer’s disease

“…Longitudinal measurement in AD mutation carriers revealed altered CSF levels 5 years before expected clinical onset, when signs of brain amyloidosis and neurodegeneration were already obvious 70 . CSF sTREM2 levels were highest at the clinical stage of MCI, compared with other stages of AD 71,72 ; increases in these levels were most pronounced immediately before the onset of dementia symptoms, when widespread neurodegeneration and synaptic loss were ongoing. Alterations in CSF sTREM2 levels were also identified in patients with other brain disorders, as well as in patients with SNAP 71 .…”

Synaptic, axonal damage and inflammatory cerebrospinal fluid biomarkers in neurodegenerative dementias

“…The antibodies for the detection of these four noncore biomarkers have been used by us and other authors on previous studies with CSF samples in neurodegenerative dementias. These biomarkers have been also individually studied using other technologies or antibodies …”

“…These biomarkers have been also individually studied using other technologies or antibodies. [37][38][39][40] All analyses were performed by duplicate and experienced laboratory personnel blinded to clinical diagnosis. We are participants of the Alzheimer's Association QC program, 41 and A 42, t-tau, and p-tau levels obtained in our laboratory have consistently been within mean ± 2SD.…”

“Amyloid‐beta accumulation cycle” as a prevention and/or therapy target for Alzheimer's disease

“…The expression and release of pro-inflammatory molecules are primarily achieved through glial cells, especially by astrocytes and microglia; glial cell functions are also involved in amyloid-beta clearance and in neurodegenerative disease conditions, including AD(Pérez-Nievas & Serrano-Pozo, 2019;Valles et al, 2019). Consistently, in cerebrospinal fluid, microglia activation marker (soluble triggering receptor expressed on myeloid cells 2 (sTREM)), a marker of microglial inflammatory reaction (monocyte chemoattractant protein-1 (MCP-1)), and astroglial activation marker (chitinase-3-like protein 1 (YKL-40)) increased as AD progressed(Nordengen et al, 2019).…”