TREM2 Research Articles

Exome sequencing identifies rare damaging variants in the ATB8B4 and ABCA1 genes as novel risk factors for Alzheimer's disease.

Damaging rare variants in the TREM2, SORL1 and ABCA7 genes have been associated with an increased risk of developing Alzheimer's Disease (AD) with odds ratios that were not observed since the identification of the main AD genetic risk factor, the APOE-ε4 allele. Here, we aimed to identify additional AD-associated genes by investigating the burden of rare damaging variants in the exomes of AD cases and controls. On a single server, we analyzed in two stages, the data from 52,270 exome sequences from several independent datasets from Europe and the United States. After comprehensive QC, Stage-1 and Stage-2 datasets comprised in total 16,396 AD cases (5,672 EOAD) and 18,107 controls with European ancestry. All detected non-synonymous and loss-of-function rare variants were prioritized by REVEL and LOFTEE, and analyzed in a per-gene burden analysis. After a Stage-1 discovery analysis, we replicated findings in an independent dataset (Stage-2). We combined the Stage-1 and Stage-2 datasets and determined, for each gene, the features of the variants that drive the burden-associations. We confirmed the AD-association of rare damaging variants SORL1, TREM2, ABCA7, and newly identified a significant AD-association of rare damaging variants in the ATP8B4 and ABCA1 genes. In addition, we find a strong indication for the AD-association of ADAM10 and SRC genes (Stage-2 p<0.05). For most genes, we observed a larger effect size for LOF variants compared to missense variants (Figure-A). High-impact variants in these genes are mostly extremely rare and enriched in AD patients with early ages at onset (Figure-B). We identified, for the first time, the AD-association of rare damaging variants in two genes: (i) microglial ATP8B4 which is involved in phospholipid transport, and (ii) ABCA1 which plays a critical role in lipidation of apoE thereby supporting Aβ processing. Further, we found strong evidence for the AD-association of damaging variants in ADAM10 and SRC genes. ADAM10 is involved in the proteolytic processing of APP, while SRC is a Non-Receptor Tyrosine Kinase which binds PTK2B/Pyk2, a known AD risk factor. Together, our study provides further evidence for the role of Aβ and microglia in AD pathophysiology.

Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer's disease.

The roles of APOEε4 and APOEε2-the strongest genetic risk and protective factors for Alzheimer's disease-in glial responses remain elusive. We tested the hypothesis that APOE alleles differentially impact glial responses by investigating their effects on the glial transcriptome from elderly control brains with no neuritic amyloid plaques. We identified a cluster of microglial genes that are upregulated in APOEε4 and downregulated in APOEε2 carriers relative to APOEε3 homozygotes. This microglia-APOE cluster is enriched in phagocytosis-including TREM2 and TYROBP-and proinflammatory genes, and is also detectable in brains with frequent neuritic plaques. Next, we tested these findings in APOE knock-in mice exposed to acute (lipopolysaccharide challenge) and chronic (cerebral β-amyloidosis) insults and found that these mice partially recapitulate human APOE-linked expression patterns. Thus, the APOEε4 allele might prime microglia towards a phagocytic and proinflammatory state through an APOE-TREM2-TYROBP axis in normal aging as well as in Alzheimer's disease.

Susceptibility to Neurodegenerative Disorders: Insights from Paleogenomic Data

abstract: Ancient human genome data accumulated in recent years can be employed to establish the spatiotemporal trajectories of genetic variants associated with human diseases. Such knowledge might illuminate if and how past adaptations impact contemporary human health and medicine. Scarcely any studies have yet attempted to evaluate genetic susceptibility to neurodegenerative disorders in ancient human communities. Using publicly available ancient human genome-wide data, this study evaluated the molecular predisposition to neurodegenerative disorders in ancient human communities. Ancient genome-wide data was screened for the presence of variants unequivocally associated with neuro-degenerative disorders in modern populations, identifying two rare variants in the LRRK2 gene associated with Mendelian Parkinson’s disease, a pathogenic variant in the CRH gene associated with an uncommon form of epilepsy, and a rare variant in the TREM2 gene that is a possible risk modifier associated with Alzheimer’s disease. Their historical and geographic prevalence was also assessed, indicating differing spatiotemporal frequency dynamics for these clinically significant variants. Neurodegenerative disorders often have poorly understood pathogenesis that might be elucidated by studying the interaction of past genetic variability with ecological and evolutionary factors such as adverse environmental conditions, specific selective pressures, periods of population isolation, and admixture processes. Data on molecular predisposition to neurodegenerative disorders in ancient genomes is instructive to modern medical diagnostic and therapeutic practices.

The Association between TREM2 Gene and Late-Onset Alzheimer’s Disease in Chinese Han Population

Objective: : The objective of this study was to evaluate the impact of single nucleotide polymorphisms (SNPs) in triggering receptor expressed on the myeloid cells 2 protein (TREM2) gene and their interaction with environmental factors and haplotypes on late-onset Alzheimer’s disease (LOAD). Methods: DNA was extracted from the whole blood of the participants and genotyped using PCR and followed by restriction fragment length polymorphism. The Hardy-Weinberg equilibrium test was used in the control group. Multivariate logistic regression analysis was used to determine the relationship between the 4 SNPs of the TREM2 gene and the risk of LOAD. Generalized multifactor dimensionality reduction was used to test the best interaction combination between SNPs and environmental factors. Results: Logistic regression analysis showed that the T allele of rs75932628 and the T allele of rs2234253 were independently associated with increased risk of LOAD, and adjusted odds ratios (ORs) were 1.81 (1.271–2.35) and 1.59 (1.15–2.03), respectively. However, there was no significant association with LOAD for rs142232675 and rs143332484. We found a best model significantly associated with LOAD risk that consisted of rs75932628 and smoking, which scored 10/10 for both the sign test and cross-validation consistency (p = 0.012). Stratified analysis indicated that current smokers with rs75932628-CT/TT genotype have the highest LOAD risk compared to never smokers with rs75932628 – CC genotype, OR (95% confidence interval) = 2.73 (1.72–3.79). Haplotypes of rs75932628 and rs2234253 were analyzed using the SHEsis online software. However, no haplotype was found to be significantly associated with the risk of LOAD. Conclusions: The T allele of rs75932628 and the T allele of rs2234253 and interaction between rs75932628 and smoking were all correlated with increased risk of LOAD.

Role of TREM2 in Alzheimer's Disease: A Long Road Ahead.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by an increasing deterioration of memory, which is concomitant with additional cognitive deficits. Neurofibrillary tangles and senile plaques are two pivotal proteins inside the brain that are considered essential to obstruct the normal cognitive function of the brain. Genetic variations in TREM2 gene disturb the neuroinflammatory action of microglia in reducing the progression of the disease.TREM2 is a transmembrane receptor present on the microglia, which has an important function in neuroinflammation. Genome-wide association studies identified variants of TREM2 gene and linked it with the risk of developing AD, by 2-4 folds. Numerous studies on mice models have revealed the relationship between mutations of TREM2 gene and its effect on amyloid burden and tau pathology in the brain that gets affected by AD. This review summarizes the role of TREM2 and its variants in the progression of AD and tries to delve deep into the role of soluble TREM2 as an effective biomarker and impending neuroprotection in AD. It also focuses on the strategies to develop therapeutic agents against TREM2 by employing its expression, function, and signalling pathways. The current challenges posed against prospective therapy for AD are also discussed.

Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice

Heterozygous genetic variants within the TREM2 gene show a strong association with increased Alzheimer's disease (AD) risk. Amyloid beta-depositing mouse models haploinsufficient or null for Trem2 have identified important relationships among TREM2, microglia, and AD pathology; however, results are challenging to interpret in the context of varying microglial phenotypes and disease progression. We hypothesized that acute Trem2 reduction may alter amyloid pathology and microglial responses independent of genetic Trem2 deletion in mouse models. We developed antisense oligonucleotides (ASOs) that potently but transiently lower Trem2 messenger RNA throughout the brain and administered them to APP/PS1 mice at varying stages of plaque pathology. Late-stage ASO-mediated Trem2 knockdown significantly reduced plaque deposition and attenuated microglial association around plaque deposits when evaluated 1 mo after ASO injection. Changes in microglial gene signatures 1 wk after ASO administration and phagocytosis measured in ASO-treated cells together indicate that microglia may be activated with short-term Trem2 reduction. These results suggest a time- and/or dose-dependent role for TREM2 in mediating plaque deposition and microglial responses in which loss of TREM2 function may be beneficial for microglial activation and plaque removal in an acute context.

Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum.

Primary lateral sclerosis (PLS) is a motor neuron disorder characterized by a pure upper motor neuron degeneration in the bulbar and spinal regions. The key difference with amyotrophic lateral sclerosis (ALS) is the lower motor neuron system integrity. Despite important literature on this disease, the pathophysiology of PLS remains unknown, and the link with ALS still balances between a continuum and a separate entity from ALS. We report nine families in which both PLS and ALS cases occurred, in general among first-degree relatives. The patients with PLS and ALS had a typical disease presentation. Genetic studies revealed mutations in SQSMT1, TBK1, and TREM2 genes in two PLS patients and one ALS patient. These results strongly support a phenotypic continuum between PLS and ALS.

Activated microglia mitigate Aβ-associated tau seeding and spreading.

In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation.

TREM2 variants as a possible cause of frontotemporal dementia with distinct neuroimaging features.

Nasu-Hakola disease (NHD) is a rare, autosomal recessive disorder characterized by skeletal and neurological symptoms. Behavioral symptoms with cognitive impairment may mimic the behavioral variant of frontotemporal dementia (bvFTD) and other early-onset dementias. Our patients were analyzed and the literature was reviewed to delineate neurological and neuroimaging findings suggestive of NHD. Fourteen patients carrying a pathogenic mutation in the TREM2 gene were found in our database. Demographic, clinical, laboratory and radiological data were retrieved and analyzed. The presenting clinical picture was behavioral changes with cognitive decline resembling bvFTD in all patients. The mean age was 37.1±4.97years and the mean duration of the disease was 8.9±3.51years. Only two patients had typical bone cysts. Seven patients had bilateral calcification of the basal ganglia in computed tomography of the brain. Magnetic resonance imaging of the brain revealed severe atrophy of the corpus callosum, enlargement of the ventricles, atrophy of the caudate nuclei and periventricular white matter changes in all patients. Symmetrical global atrophy of the brain mainly affecting frontoparietal and lateral temporal regions were observed in all cases, and 13 patients had atrophy of the hippocampus. Cerebrospinal fluid examination of 10 patients showed elevated protein levels in six and the presence of oligoclonal bands in four patients. A combination of white matter changes, enlarged ventricles, atrophy of the caudate nuclei and thinning of the corpus callosum in magnetic resonance imaging strongly suggests NHD in patients with FTD syndrome. Molecular genetic analysis should be performed in suspected cases, and families should receive genetic counseling.

Disease‐modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: a comparative study with donepezil

Background and PurposeThe development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I2 imidazoline receptor ligands have a neuroprotective role in AD. Moreover, co‐treatment of AChE inhibitors with neuroprotective agents have shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I2 ligand, donepezil and their combination in 5XFAD mice.Experimental Approach5XFAD female mice were treated with low doses (1 mg·kg−1·day−1) of LSL60101, donepezil and donepezil plus LSL60101, during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze and three‐chamber tests were used to evaluate the cognitive and behavioural status after treatment. The effects on AD‐like pathology were assessed with immunohistochemistry, western blot, ELISA and qPCR.Key ResultsChronic low‐dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety‐like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil/LSL60101 treatments attenuated amyloid‐β pathology by decreasing amyloid‐β40 and amyloid‐β42 levels, amyloid‐β plaque number and tau hyperphosphorylation. These alterations were accompanied by reduced microglia marker Iba‐1 levels and increased Trem2 gene expression. LSL60101 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60101 and donepezil/LSL60101 treatments significantly increased the synaptic marker levels of post‐synaptic density protein 95 and synaptophysin.Conclusion and ImplicationsChronic low‐dose treatment with selective I2‐ ligands can be an effective treatment for AD and provide insights into combination treatments for symptomatic and disease‐modifying drugs.

Favorable tumor immune microenvironment (TME) and robust chimeric antigen receptor (CAR) T-cell expansion may overcome tumor burden (TB) and promote durable efficacy with axicabtagene ciloleucel (axi-cel) in large B-cell lymphoma (LBCL).

7536 Background: Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved for patients (pts) with relapsed/refractory LBCL after ≥2 prior systemic therapies. In the pivotal ZUMA-1 study, pts with high pretreatment (preTx) TB (estimated by sum of product diameters [SPD]) had lower peak CAR T-cell expansion normalized to TB and less frequent durable response rates vs pts with low TB ( &lt; 30% vs &gt; 60%, respectively; Blood Adv. 2020;4:3268). The number of CD8+ and CCR7+CD45RA+ product T cells infused and favorable immune contexture in preTx TME were also associated with axi-cel response ( Blood Adv. 2020;4:3268; Galon et al. ASCO 2020. #3022). As potential barriers to axi-cel efficacy are not fully elucidated, we systematically analyzed preTx TME characteristics, including myeloid-related biomarkers and product attributes, to identify such challenges in ZUMA-1 pts with high TB. Methods: Samples from evaluable pts in ZUMA-1 Phase (Ph) 1 and Ph2 Cohorts (C) 1–3 were analyzed (NCT02348216; Ph1 and Ph2 C1+2, ≥2-y follow-up; C3, ≥6-mo follow-up). PreTx immune TME was analyzed by multiplex immunohistochemistry (n = 18) and gene expression analysis (n = 30) as previously described (Rossi et al. AACR 2018. #LB-016; Galon et al. ASCO 2020. #3022). CAR T-cell product characteristics and other covariates were evaluated as previously described ( Blood Adv. 2020;4:3268). Correlative analyses of these covariates with clinical outcomes were performed by Wilcoxon or Kruskal-Wallis test. Median TB (by SPD) from ZUMA-1 Ph1 and Ph2 C1+2 was used as a cutoff for high ( &gt; 3721 mm2) vs low (≤3721 mm2) TB. Durable response refers to pts in ongoing response at time of data cutoff. Results: PreTx immune TME features related to suppressive myeloid-related activity, most notably ARG2, TREM2, and IL-8 gene expression, were elevated in pts who failed to respond or relapsed without documented loss of CD19 expression. ARG2 and TREM2 levels in preTx biopsies were negatively associated with CD8+ T-cell density. Pts with high TB who achieved durable response had low preTx ARG2 and TREM2 levels in TME and enhanced CAR T-cell expansion after axi-cel compared to pts with high TB who relapsed. High ratio of T-cell to suppressive myeloid cell markers (T/M ratio) in preTx biopsies associated positively with CAR T-cell expansion (peak and peak normalized to TB) and durable response in pts with high TB. Conclusions: Axi-cel may overcome high TB in pts with a favorable immune TME alongside robust CAR T-cell expansion. Favorable immune TME is characterized by reduced suppressive myeloid cell activity (low ARG2 and TREM2 expression) and increased T/M ratio. These data suggest possible actionable strategies to overcome high TB in the context of CAR T-cell therapy. [JC and VP contributed equally] Clinical trial information: NCT02348216.

Trem-2 Promotes Emergence of Restorative Macrophages and Endothelial Cells During Recovery From Hepatic Tissue Damage.

Macrophages are pivotal in mounting liver inflammatory and tissue repair responses upon hepatic injury, showing remarkable functional plasticity. The molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) and chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts of liver macrophages and impacts endothelial cell differentiation during tissue recovery. Trem-2 gene ablation led to a delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. During tissue recovery, we found that macrophages transitioning to Kupffer cells expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with a unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2. During tissue recovery, lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs), whose transcriptional program was compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and by striking in vitro morphological changes towards typical endothelial cells. In conclusion, we found that the dynamics of liver macrophages in response to liver injury are critically controlled by Trem-2 and this regulation is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from pro-inflammatory to tissue repair phase by driving the acquisition of restorative properties in phagocytic macrophages.

Higher TREM2 levels and microglia activation associated with slower rates of amyloid PET increase in humans and a transgenic mouse model of beta‐amyloid

AbstractBackgroundLoss‐of‐function mutations in the TREM2 gene, a key receptor molecule on microglia, are associated with a 2 – 3 fold increase in the risk of Alzheimer’s disease (AD). Biomarker‐levels of soluble TREM2 (sTREM2) are increased in AD and associated with slower cognitive decline, suggesting a protective role of sTREM2‐related microglia activity (Suarez Calvet et al. Science Trans Med, 2016; Ewers et al. Science Trans Med., 2019). However, whether microglia activity reduces the future accumulation of core AD‐pathology remains unclear. Here we 1) tested in elderly subjects whether higher cerebrospinal fluid (CSF) levels of sTREM2 are associated with slower longitudinal rates of global amyloid‐PET accumulation, and 2) in a transgenic mouse model of Ab, whether higher baseline microglia‐PET is associated with slower rates of amyloid‐PET accumulation.Method206 Ab‐positive participants (global 18F‐AV‐45‐PET SUVR &gt; 0.79, Landau et al. 2015) comprising 55 cognitively normal, 136 amnestic mild cognitive impairment and 15 AD dementia participants, and in addition, 94 Ab‐negative CN were included from ADNI. CSF sTREM2 and 18F‐AV‐45 PET were measured at baseline, and 18F ‐AV‐45 PET was repeated during follow‐up (mean = 2 years, range = 1.71‐6.1 years). 15 APPNL‐G‐F transgenic mice and 43 age‐ and gender matched C57BL/6 control mice were assessed with 18F‐GE180 TSPO‐PET at age 5 months and 18F‐AV‐45 PET at ages 5 and 10 months.ResultIn linear mixed effects analysis across all participants, the rate of change in amyloid PET showed a quadratic curve as a function of baseline amyloid‐PET levels, peaking at SUVR = 0.95 (Fig. 1A). Baseline levels of CSF sTREM2 modulated the rate of change in amyloid‐PET, such that at higher CSF sTREM2, the rate of subsequent increase in amyloid‐PET was reduced, controlled for demographics, diagnosis, CSF p‐tau181, and ApoE e4 (Figure 1B). In the AppNL‐G‐F mice, higher microglia‐PET at baseline was associated with slower rate of increase in global amyloid‐PET increase, controlled for baseline amyloid‐PET (Figure 2).ConclusionAcross humans and mice, higher microglia activation as measured by CSF sTREM2 or microglia PET showed protective effects on subsequent amyloid accumulation, supporting the critical role of microglia activation in the development of AD.

Exome sequencing identifies three novel AD‐associated genes

AbstractBackgroundWith the development of next‐generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimer’s Disease (AD), reaching odds ratios comparable with the main AD genetic risk factor, the APOE‐ε4 allele. Here, we set out to identify additional AD‐associated genes by a genome‐wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls, the largest AD‐WES dataset available worldwide.MethodWe integrated the data from 25,982 cases and controls from the European ADES consortium and ADSP consortium from the USA on a single server. We developed a unique bioinformatic pipeline that applies new techniques to homogenize and analyze these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of AD were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analyzed using a burden analysis, using both non‐synonymous and loss‐of‐function rare variants. Variant impact was prioritized using REVEL.ResultIn our discovery phase, we confirmed and further substantiated that carriership of protein‐damaging genetic variants in TREM2, SORL1 or ABCA7 is a major AD‐risk factor. High‐impact variants in these genes are mostly extremely rare and they are enriched in AD patients with early ages at onset. Furthermore, we identified three additional genes that were significantly associated with AD, in which we identified a similar relationship between very rare, high‐impact variants and an enrichment in AD patients with early ages at onset. We are currently replicating these associations and several additional suggestive findings in independent datasets. The final results will be presented.ConclusionDevelopment of new homogenization methods has enabled the combined analysis of the largest AD‐WES dataset worldwide. With this, we were able to validate and expand on previous findings and to identify new genetic determinants of AD. Together, these genes pinpoint the most relevant pathways in the pathophysiological processes leading to AD.

Targeting TREM2 to enhance immunotherapy

Targeting TREM2 to enhance immunotherapy

TREM2 activation promotes remyelination.

Cignarella, F. et al. TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis. Acta Neuropathol. https://doi.org/10.1007/s00401-020-02193-z (2020) Article PubMed Google Scholar Ulland, T. K. & Colonna, M. TREM2 — a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14, 667–675 (2018) CAS Article Google Scholar Download references Nature Reviews Neurology Heather Wood You can also search for this author in PubMed Google Scholar Correspondence to Heather Wood. Reprints and Permissions Wood, H. TREM2 activation promotes remyelination. Nat Rev Neurol (2020). https://doi.org/10.1038/s41582-020-0404-9 Download citation Published: 24 August 2020 DOI: https://doi.org/10.1038/s41582-020-0404-9

A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study.

Purpose The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered “disease causing.” In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.

Amyloid-beta (1-42) lesion of CA1 rat dorsal hippocampus reduces contextual fear memory and increases expression of microglial genes regulating neuroinflammation

Emerging evidence indicates that the pathogenesis of Alzheimer’s disease (AD) is not confined to neuronal disruptions but robustly communicates with the brain’s immune system. Genome-wide analysis suggests that several genes, which increase the risk for AD, encode for factors that regulate the glial clearance of misfolded proteins and the inflammatory reaction. This study reappraises the amyloid hypothesis by focusing on the impact of neuroinflammation in a beta-amyloid model of AD, how this possibly exacerbates the disease's progression, and the correlation between genes regulating neuroinflammation (CD33 and TREM2) with post-training recall. Male Sprague-Dawley rats were used for this study, randomly divided into a vehicle group of rats (n = 40) that were infused with phosphate-buffered saline (PBS) and an Aβ(1–42) group (n = 40) that were infused with the neurotoxin Aβ(1–42) peptide. Fear conditioning test (FCT) to assess fear memory was conducted pre and post-lesion. The polymerase chain reaction was performed to determine the expression levels of CD33 and TREM2 genes. Our results show that Aβ(1–42) lesion of the rat CA1 hippocampal subregion significantly reduces contextual fear memory, and this reduction was exacerbated as the post-lesion days increased. We also observed an increase in the expression levels of CD33 and TREM2 genes in the Aβ(1–42) lesioned groups compared to their corresponding vehicle groups. Taken together, the behavioral and gene expression data provide inferential evidence that Aβ(1–42) infusion impairs contextual memory by disrupting cellular pattern separation processes in the hippocampus, thus linking neuroinflammation to specific neural circuit disruption and cognitive deficit.

NMR backbone assignment of the transmembrane helix of TREM2, an Alzheimer linked disease protein

NMR backbone assignment of the transmembrane helix of TREM2, an Alzheimer linked disease protein

Assessment of TREM2 rs75932628 variant’s association with Parkinson’s disease in a Greek population and Meta-analysis of current data

Background Α number of genetic variants are considered to confer susceptibility to Parkinson’s disease (PD). Rs75392628 (R47H), a rare variant of TREM2 gene, has been linked to PD, although its role on PD remains conflicting. Objective Detection of a possible contribution of rs75392628 variant of TREM2 gene to PD risk. Methods A total of 358 PD patients and 358 healthy controls genotyped for rs75392628. In addition, a meta-analysis was performed by merging our results with those from previous studies. Results The rare variant of rs75932628 (47H) of TREM2 gene was not detected on cohort. Meta-analysis of a total of 9271 PD cases and 9777 controls across 14 independent PD data sets from 9 studies, including the present study, did not show any statistically significant effect of rs75392628 on PD risk (ORFE:1.54 95% CI:0.87-2.73. ORRE: 1.54, 95%CI: 0.71-3.32). Conclusions Rs75392628 TREM2 variant is rather unlikely to be a major genetic risk contributor of PD.