Profiling TREM2 expression in amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: There is growing evidence of the contribution of neuroinflammation, and in particular microglia, in the pathogenesis of amyotrophic lateral sclerosis (ALS). TREM2 gene plays a crucial role in shaping microglia in neurodegenerative conditions. To deepen the understanding of TREM2 in ALS and investigate the performance of TREM2 as a biomarker, we profiled TREM2 expression levels in spinal cord, cerebrospinal fluid and blood of patients with sporadic ALS. We also wanted to investigate whether the combined measurement of sTREM2 in fluids could improve the diagnostic yield of total and phosphorylated TDP-43 levels. METHODS: We performed a case-control study to profile overall and transcript-specific TREM2 mRNA levels by RT-qPCR and protein expression levels by Western-blot in postmortem specimens of spinal cord from ALS patients and controls. In parallel, we measured soluble TREM2 (sTREM2) protein levels and full length and phosphorylated TDP-43 (tTDP-43 and pTDP-43) by ELISA in CSF and serum from ALS patients vs healthy controls. Patients were prospectively recruited from an ALS unit of a tertiary hospital and fulfilled El Escorial revised criteria. After bivariate analysis, a logistic regression model was developed to identify adjusted estimates of the association of sTREM2 levels in CSF and serum with ALS status. RESULTS: Overall and transcript-specific TREM2 mRNA were upregulated in the spinal cord of ALS patients (n = 21) compared to controls (n = 19). Similar changes were observed in TREM2 protein levels (p < 0.01) in spinal cord of ALS patients vs healthy controls. We also detected significantly higher sTREM2 levels in CSF (p-value < 0.01) of ALS patients (n = 46) vs controls (n = 46) and serum (p-value < 0.001) of ALS patients (n = 100) vs controls (n = 100). In a logistic regression model, both CSF and serum sTREM2 remained independently associated with ALS status with OR = 3.41 (CI 95 %=1.34-8.66) (p-value < 0.05) and OR = 3.38 (CI 95 %: 1.86-6.16) (p-value < 0.001), respectively. We also observed that pTDP-43 levels in CSF is an independent predictor of ALS (p-value < 0.05). CONCLUSIONS: Our results support the role of TREM2 in ALS pathophysiology and demonstrates that the three TREM2 transcripts are deregulated in ALS in postmortem human specimens of spinal cord. We hypothesise about the possible influence of systemic-peripheral inflammation in the disease. Finally, we conclude that pTDP-43 levels in CSF could be a biomarker of ALS, and sTREM2 measurement in CSF and blood emerge as potential non-invasive biomarker in ALS.

Early epigenetic changes of Alzheimer's disease in the human hippocampus.

The discovery of new biomarkers would be very valuable to improve the detection of early Alzheimer's disease (AD). DNA methylation marks may serve as epigenetic biomarkers of early AD. Here we identified epigenetic marks that are present in the human hippocampus from the earliest stages of AD. A previous methylome dataset of the human AD hippocampus was used to select a set of eight differentially methylated positions (DMPs) since early AD stages. Next, bisulphite pyrosequencing was performed in an expanded homogeneous cohort of 18 pure controls and 35 hippocampal samples with neuropathological changes of pure AD. Correlation between DNA methylation levels in DMPs and phospho-tau protein burden assessed by immunohistochemistry in the hippocampus was also determined. We found four DMPs showing higher levels of DNA methylation at early AD stages compared to controls, involving ELOVL2, GIT1/TP53I13 and the histone gene locus at chromosome 6. DNA methylation levels assessed by bisulphite pyrosequencing correlated with phospho-tau protein burden for ELOVL2 and HIST1H3E/HIST1H3 F genes. In this discovery study, a set of four epigenetic marks of early AD stages have been identified in the human hippocampus. It would be worth studying in-depth the specific pathways related to these epigenetic marks. These early alterations in DNA methylation in the AD hippocampus could be regarded as candidate biomarkers to be explored in future translational studies. ABBREVIATIONS: AD: Alzheimer's disease; DMPs: Differentially methylated positions; CSF: Cerebrospinal fluid; ßA42: ß-amyloid 42; PET: positron emission tomography; 5mC: 5-methyl cytosine; CpG: cytosine-guanine dinucleotides; ANK1: ankyrin-1; BIN1: amphiphysin II; p-tau: hyperphosphorylated tau; CERAD: Consortium to Establish A Registry for Alzheimer's Disease; SD: standard deviation; ANOVA: one-way analysis of variance; VLCFAs: very long-chain fatty acids; DHA: docosahexaenoic acid; mTOR: mechanistic target of rapamycin.

Microglia-Related Gene Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) Is Upregulated in the Substantia Nigra of Progressive Supranuclear Palsy.

BACKGROUND: The role of the microglia-related gene triggering receptor expressed in myeloid cells 2 (TREM2) in primary tauopathies, such as progressive supranuclear palsy (PSP), still remains unclear. OBJECTIVES: The objective of this study was to profile overall and transcript-specific TREM2 expression levels in the substantia nigra (SN) of PSP patients and controls. METHODS: SN samples from neuropathologically confirmed PSP cases (n = 24) and controls (n = 14) were used to measure TREM2 and TREM2-modulating gene Membrane-spanning 4-domains subfamily A member 4A (MS4A4A) mRNA levels by real-time quantitative polymerase chain reaction. Correlation with hyperphosphorylated tau protein burden was assessed. RESULTS: Overall TREM2 and each of the 3 TREM2 transcripts mRNA levels were significantly increased in the SN of PSP cases versus controls. TREM2 mRNA levels positively correlated with hyperphosphorylated tau burden in SN, specifically in neurons. The MS4A4A gene was also upregulated in PSP patients versus controls. CONCLUSIONS: These results add evidence to the involvement of microglia in the disease process of PSP. These findings support the idea that different tauopathies may share common patterns of deregulation in innate immune molecular pathways. © 2020 International Parkinson and Movement Disorder Society.