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A Candidate Regulatory Variant at the TREM Gene Cluster Confer Alzheimer's Disease Risk by Modulating Both Amyloid-Β Pathol

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A Candidate Regulatory Variant at the TREM Gene Cluster Confer Alzheimer's Disease Risk by Modulating Both Amyloid-Β Pathol fnins-13-00742 July 15, 2019 Time: 15:26 # 1 ORIGINAL RESEARCH published: 17 July 2019 doi: 10.3389/fnins.2019.00742 A Candidate Regulatory Variant at Edited by: the TREM Gene Cluster Confer Robert W. Williams, The University of Tennessee Health Science Center (UTHSC), Alzheimer’s Disease Risk by United States Reviewed by: Modulating Both Amyloid-b Rossen Donev, MicroPharm Ltd., United Kingdom Pathology and Neuronal Jun Xu, Capital Medical University, China Degeneration *Correspondence: Lan Tan Mei-Ling Tian1, Xiao-Neng Ni2, Jie-Qiong Li1, Chen-Chen Tan1, [email protected] Xi-Peng Cao3 and Lan Tan2,3* for the Alzheimer’s Disease Neuroimaging Initiative† †The data used in the preparation of 1 Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China, 2 Department of Neurology, this article were obtained from the Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China, 3 Clinical Research Center, Qingdao Municipal Alzheimer’s Disease Neuroimaging Hospital, Qingdao University, Qingdao, China Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI Background: rs9357347 located at the triggering receptor expressed on myeloid cells contributed to the design and implementation of ADNI and/or (TREM) gene cluster could increase TREM2 and TREM-like transcript 1 (TREML1) provided data but did not participate brain gene expression, which is considered to play a protective role against in the analysis or writing of this report. Alzheimer’s disease (AD). A complete listing of ADNI investigators can be found at: Objectives: To investigate the role of rs9357347 in AD pathogenesis by exploring the http://adni.loni.usc.edu/wp-content/ uploads/how_to_apply/ADNI_ effects of rs9357347 on AD specific biomarkers. Acknowledgement_List.pdf Methods: This study analyzed the association of rs9357347 with AD-related Specialty section: cerebrospinal fluid (CSF) and neuroimaging markers from 201 cognitively normal (CN) This article was submitted to older adults, 349 elders with mild cognitive impairment (MCI), and 172 elders with AD Neurogenomics, a section of the journal dementia from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We next analyzed Frontiers in Neuroscience the association in 259 amyloid-b positive (AbC) elders and 117 amyloid-b negative (Ab−) Received: 14 September 2018 elders (AbC: CSF Ab1−42 ≤ 192 pg/ml; Ab−: CSF Ab1−42 > 192 pg/ml). Associations Accepted: 04 July 2019 Published: 17 July 2019 were tested using multiple linear regression models at baseline. Furthermore, multiple Citation: mixed-effects models were used in a longitudinal study which lasted 4 years. Tian M-L, Ni X-N, Li J-Q, Tan C-C, Results: At baseline, we found that rs9357347 had association with CSF Ab − in Cao X-P and Tan L for the Alzheimer’s 1 42 Disease Neuroimaging Initiative (2019) CN group (b = 0.357, P = 0.009). In AD group, rs9357347 was associated with total A Candidate Regulatory Variant tau (T-tau) level (b = −0.436, P = 0.007). Moreover, the strong influence exerted by at the TREM Gene Cluster Confer Alzheimer’s Disease Risk by rs9357347 on T-tau was also seen in AbC group (b = −0.202, P = 0.036). In the Modulating Both Amyloid-β Pathology longitudinal study, rs9357347 was also found to be associated with Ab1−42 in CN and Neuronal Degeneration. group (b = 0.329, P = 0.023). In AD group, the mutation of rs9357347 was associated Front. Neurosci. 13:742. doi: 10.3389/fnins.2019.00742 with slower accumulation of T-tau (b = −0.472, P = 0.002) and tau phosphorylated at Frontiers in Neuroscience| www.frontiersin.org 1 July 2019| Volume 13| Article 742 fnins-13-00742 July 15, 2019 Time: 15:26 # 2 Tian et al. TREM Gene and Neuronal Degeneration threonine 181 [P-tau 181 (b = −0.330, P = 0.019)]. Furthermore, the obvious influence exerted by rs9357347 on T-tau was also seen in AbC group (b = −0.241, P = 0.013). Conclusion: This study suggested that rs9357347 reduced the risk of AD by modulating both amyloid-b pathology and neuronal degeneration. Keywords: Alzheimer’s disease, TREM2 gene, TREML1, rs9357347, genetic mechanism, cerebrospinal fluid, amyloid-b pathology, neuronal degeneration INTRODUCTION Our ADNI cohort consisted of available baseline and longitudinal AD-related marker samples from all cognitively Alzheimer’s disease (AD) is a complex polygenetic disease normal (CN) elders, patients with MCI, and patients with AD characterized by the presence of extracellular deposits of the dementia. Inclusion or exclusion criteria are described in detail amyloid-b1−42 (Ab1−42) and intracellular twisted strands of on pages 20–22 of the online ADNI protocol. Briefly, all subjects the tau protein (Alzheimer’s Association, 2011). In the genetic were aged from 55 to 90 years old, kept contact with their study studies, the triggering receptor expressed on myeloid cells partners 10 h per week or more, had completed at least six (TREM) gene cluster on chromosome 6p21.11 has been identified grades of education or had a good employment history, spoke as significantly associated gene region with AD (Karch et al., English or Spanish fluently, and were removed of any significant 2014). Among the TREM genes, a rare variant rs75932628 neurological disease other than AD (Petersen et al., 2010). Any (encoding p. Arg47His) in TREM2 was reported to be associated history of head trauma or brain lesions, any serious neurological with the highest risk of developing AD in Caucasians (Colonna, disease other than probable AD, and any psychoactive medication 2003; Piccio et al., 2007). use that could otherwise account for the deterioration in memory Recently, Carrasquillo et al.(2017) re-analyzed whole genome and related symptoms must be excluded (Jagust et al., 2009; and exome sequencing data to test which common AD-related Weigand et al., 2011). variants within the TREM gene cluster influence AD through We used two classification criteria for the 722 ADNI samples gene expression. rs9357347, located downstream from TREML2 to study the association of rs9357347 allele with AD dementia. and upstream from TREM2, was found to be associated with AD One is clinical classification (AD, MCI, CN groups) which risk (Carrasquillo et al., 2017). And the locus was demonstrated to includes 201 CN older adults, 349 elders with MCI, and influence TREML1 and TREM2 expression in the temporal cortex 172 elders with AD dementia. And another is pathological (Ford and McVicar, 2009). Meanwhile, they found that only classification classifying the subjects into two groups according to TREM2 and TREML1 had reliable expression in the brain region. previously established cutoff. It has been shown that individuals CC Thus, they point out that rs9357347 exerts protective effects on with CSF Ab1−42 levels less than 192 pg/ml in the ADNI AD through increasing TREML1 and TREM2 brain expression cohort have evidence of Ab1−42 deposition in the brain, as levels. However, the specific pathogenic effect rs9357347 exerts detected by PET-PIB (Fagan et al., 2007; Mattsson et al., 2009). on AD remains unclear. Therefore, the current study was to Individuals with CSF Ab1−42 levels below these thresholds (CSF test associations of rs9357347 with AD-related cerebrospinal Ab1−42 ≤ 192 pg/ml) could be classified as Ab-positive (AbC), fluid (CSF) and neuroimaging markers in the population from otherwise (CSF Ab1−42 > 192 pg/ml) they will be classified as Alzheimer’s Disease Neuroimaging Initiative (ADNI). Ab-negative (Ab−)(Olsson et al., 2005; Jack et al., 2008; Shaw et al., 2009). Thus, 259 AbC elders and 117 Ab− elders were selected from ADNI database. MATERIALS AND METHODS CSF Biomarkers Study Design and Participants The CSF data used in this study were obtained from ADNI Data used in this study were obtained from the ADNI database dataset. CSF sampled by lumbar puncture was gathered led by Principal Investigator Michael W. Weiner, MD, which into collection tubes, and then transferred to polypropylene is a public-private partnership, launched in 2003. The main conveying tubes. After collection, the samples were frozen goal of ADNI has been to test whether clinical and cognitive on dry ice within 60 min and transported immediately to assessment, positron emission tomography (PET), CSF, serial the ADNI Biomarker Core laboratory at the University of magnetic resonance imaging (MRI), and other biological markers Pennsylvania Medical Center. Preparation of aliquots (0.5 ml) can be combined to evaluate the progression of mild cognitive from these samples was done after unfreezing (60 min) at room impairment (MCI) and early AD. Written informed consent temperature and gentle mixing (Weigand et al., 2011). The was obtained from all participants or their guardians before aliquots were stored in bar code-labeled polypropylene vials test samples being drawn. The institutional review boards at −80◦C(Shaw et al., 2009). The multiplex platform (xMAP; of all sites participating in the ADNI provided review and Luminex Corporation) with a kit (INNO-BIA AlzBio3; Fujirebio approval of the ADNI data collection protocol. For more details, Europe) was used for simultaneous measurement of the CSF see www.adni-info.org. protein biomarkers such as Ab1−42, total tau (T-tau), and tau Frontiers in Neuroscience| www.frontiersin.org 2 July 2019| Volume 13| Article 742 fnins-13-00742 July 15, 2019 Time: 15:26 # 3 Tian et al. TREM Gene and Neuronal Degeneration phosphorylated at threonine 181 (P-tau 181). More details for gender, APOE +4 genotype and educational level, and the CSF acquisition and measurement have been reported previously regression analysis of brain structure volume was also corrected (Olsson et al., 2005). for intracranial volume. All statistical analyses were performed by R3.2.05. Brain Structures on MRI The volumes of brain structures in MRI used in our study were from the UCSF data in ADNI dataset1. Firstly, we downloaded RESULTS preprocessed MRI data from Laboratory of Neuroimaging (LONI) IDA2 with 1.5T or 3T data available.
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