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The triggering receptor expressed on myeloid cells 2 (TREM2) gene has been reported to increase the risk of Alzheimer's disease (AD). The soluble TREM2 protein (sTREM2) in cerebrospinal fluid (CSF) was also associated with AD. However, the role of sTREM2 in AD and its genetic modifiers remain unclear. We carried out a genome-wide association study for CSF sTREM2 levels using participants from the Alzheimer's Disease Neuroimaging Initiative and validated the significant association in an independent cohort from Chinese Alzheimer's Biomarker and LifestylE study. rs7232 in membrane spanning 4-domains A6A (MS4A6A) gene was associated with CSF sTREM2 levels at genome-wide significance (p = 1.42 × 10−15). The locus influences CSF sTREM2 levels especially in nondemented individuals. And the association was replicable in the validation cohort from Chinese Alzheimer's Biomarker and LifestylE study (p = 0.0106). Besides, the expressions of MS4A6A and TREM2 were correlated in brain regions (p

As a major characteristic of aging process, neuroinflammation is involved in the pathogenesis of several aging-related diseases including Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a newly identified risk gene for AD, which regulates inflammatory process in peripheral tissues via modulating the release of inflammatory cytokines. However, the role of TREM2 in aging-related neuroinflammation, cognitive deficiency, and AD-like neuropathology is unclear so far. Here, we detected the protein levels of TREM2 in brain of 3-, 7-, and 11-month-old senescence-accelerated mouse prone 8 (SAMP8) mice and observed that TREM2 levels were increased during aging process. We then knocked down TREM2 expression in brain of SAMP8 mice by nonviral RNA interference and found a significant increase in proinflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-6, which was accompanied by a reduction in IL-10. Meanwhile, more obvious neuronal and synaptic losses and cognitive impairment were observed. These findings indicate that TREM2 may play a protective role against aging-related neuroinflammation and cognitive impairment.

Neurodegenerative diseases, such as Alzheimer's disease Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation.

Tau pathology is a pathological hallmark for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. As a novel susceptibility gene for these 2 diseases, triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes an immune receptor that is uniquely expressed by microglia. Recently, a correlation between TREM2 expression and hyperphosphorylated tau has been revealed in the brain of Alzheimer's disease patients, suggesting a potential association between TREM2 and tau pathology. However, the role of TREM2 in tau pathology remains unclear thus far. Herein, using P301S mice, we showed that TREM2 was upregulated in microglia during disease progression. Silencing of brain TREM2 exacerbated tau pathology in P301S mice. This exacerbation might be attributed to neuroinflammation-induced hyperactivation of tau kinases. Additionally, more severe neurodegenerative changes and spatial learning deficits were observed following TREM2 silencing. Our results imply that TREM2 attenuates tau kinase activity through restriction of neuroinflammation, and thus protects against tau pathology. These findings further suggest that TREM2 may represent as a potential therapeutic target for tau-related neurodegenerative diseases.

Complement receptor 1 (CR1) has been considered to play an important role in late-onset Alzheimer's disease (LOAD) pathogenesis. To explore the correlation between the CR1 gene and LOAD, a 2-step design study was conducted in our Northern Han Chinese population. We first sequenced the promoter, exons, the 5′ and 3′ untranslated regions and exon–intron boundaries of CR1 in a small sample (n = 100). This allowed us to identify a total of 22 variants. In addition, 6 missense variants within the CR1 gene were selected to be genotyped in a total of 2292 individuals. Only 2 SNPs (rs116806486, Thr→Ala; rs6691117, Ile→Val) were significantly associated with an increased risk of LOAD. After stratification by APOE e4–carrying status, significance was observed in APOE e4 non-carriers for rs116806486 and in APOE e4 carriers for rs6691117. Logistic analysis revealed that the rs116806486 polymorphism remained associated with LOAD in a dominant model, whereas the rs6691117 polymorphism was associated with LOAD in additive and recessive models but not in a dominant model after adjusting for sex, age at onset, and APOE e4 status. Examination of the haplotypes identified the risk of a 3-SNP (rs2274567, rs3737002, and rs6691117) haplotype “ATG” in CR1 was associated with an increased risk for LOAD. These findings provide the evidence that missense variants in the CR1 gene may be involved in LOAD pathologic process in Han Chinese.

Recent studies have reported that a rare mutation of triggering receptor expressed on myeloid cells 2 gene (TREM2 [rs75932628-T]) has significantly increased the risk of late-onset Alzhemier's disease (LOAD) in European-descendent population. To date, no study has investigated the association between rare mutations of TREM2 and LOAD risk in non-European population. Here, we sequenced exon2 of TREM2 in the northern Han Chinese population consisting of 1133 patients with LOAD and 1159 control subjects. Although, 4 novel mutations (c.102G>A: Val34Val, c.330C>T: Cys110Cys, c.342T>C: His114His, and c.343G>A: Gly115Ser) were identified in patients with LOAD, none of them exhibited significant association with LOAD risk after Bonferroni correction. Most importantly, the previously reported rare variants in European-descendent population including rs75932628-T (predicted to cause an R47H substitution) were absent in our cohort. These findings suggest that mutations in exon2 of TREM2 were unlikely to play a key role in the susceptibility of LOAD in the northern Han Chinese population.

Two recent studies have identified that a rare coding variant (p.R47H) in exon 2 of triggering receptor expressed on myeloid cells 2 (TREM2) gene is associated with Alzheimer's disease (AD) susceptibility in Caucasians. This association was not successfully replicated in Han Chinese, where this variant was rare or even absent. Previously, we resequenced TREM2 exon 2 to investigate whether additional rare variants conferred risk to AD in our cohort. Although several new variants had been identified, none of them was significantly associated with disease susceptibility. Here, to test whether TREM2 is truly a susceptibility gene of AD in Han Chinese, we extend our previous study by sequencing the other four exons of TREM2 in 988 AD patients and 1,354 healthy controls. We provided the first evidence that a rare coding variant (p.H157Y) in TREM2 exon 3 conferred a considerable risk of AD in our cohort (Pcorrected = 0.02, odds ratio = 11.01, 95% confidence interval: 1.38–88.05). This finding indicates that rare coding variants of TREM2 may play an important role in AD in Han Chinese.

The current study was conducted to investigate the association of phosphatidylinositol-binding clathrin assembly protein gene (PICALM) with late-onset Alzheimer's disease (LOAD) risk in Han Chinese. We first sequenced PICALM for variants in a small sample (n = 100), and the selected variants were then genotyped in a larger cohort (n = 2292). Sequencing analysis identified 16 variants within PICALM including 5 new variants with extreme low frequency in the northern Han Chinese population. However, in the subsequent genotyping, none showed a significant association with LOAD risk after Bonferroni correction. These findings implicate that PICALM might not play a major role in the genetic predisposition to LOAD in Han Chinese.