Dysregulated Fc gamma receptor–mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis

Park, Young Ho; Risacher, Shannon L.; Lin, Kuang; Jang, Jae‐Won; Ahn, Soyeon; Kim, SangYun; Lovestone, Simon; Simmons, Andrew; Weiner, Michael W.; Saykin, Andrew J.; Nho, Kwangsik

doi:10.1016/j.neurobiolaging.2019.12.001

Cited by 39 publications

(25 citation statements)

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“…Killer inhibitory receptors similar to KIR222 and KIR3DP1 that may function in cell clearance were associated with Alzheimer’s disease [ 102 , 103 ]. Protein Kinase C Delta (PRKCD) is associated with a dysregulated Fc Gamma Receptor-mediated phagocytosis pathway in Alzheimer’s disease [ 104 ]. Genomic variants of Histone Methyl-Lysine Binding Protein 2 (L3MBTL2) that may function in the survival of motor neurons were significantly associated with AD [ 105 ].…”

Section: Discussionmentioning

confidence: 99%

The plasma peptides of Alzheimer’s disease

Florentinus-Mefailoski

Bowden

Scheltens

et al. 2021

Clin Proteom

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Background A practical strategy to discover proteins specific to Alzheimer’s dementia (AD) may be to compare the plasma peptides and proteins from patients with dementia to normal controls and patients with neurological conditions like multiple sclerosis or other diseases. The aim was a proof of principle for a method to discover proteins and/or peptides of plasma that show greater observation frequency and/or precursor intensity in AD. The endogenous tryptic peptides of Alzheimer’s were compared to normals, multiple sclerosis, ovarian cancer, breast cancer, female normal, sepsis, ICU Control, heart attack, along with their institution-matched controls, and normal samples collected directly onto ice. Methods Endogenous tryptic peptides were extracted from blinded, individual AD and control EDTA plasma samples in a step gradient of acetonitrile for random and independent sampling by LC–ESI–MS/MS with a set of robust and sensitive linear quadrupole ion traps. The MS/MS spectra were fit to fully tryptic peptides within proteins identified using the X!TANDEM algorithm. Observation frequency of the identified proteins was counted using SEQUEST algorithm. The proteins with apparently increased observation frequency in AD versus AD Control were revealed graphically and subsequently tested by Chi Square analysis. The proteins specific to AD plasma by Chi Square with FDR correction were analyzed by the STRING algorithm. The average protein or peptide log10 precursor intensity was compared across disease and control treatments by ANOVA in the R statistical system. Results Peptides and/or phosphopeptides of common plasma proteins such as complement C2, C7, and C1QBP among others showed increased observation frequency by Chi Square and/or precursor intensity in AD. Cellular gene symbols with large Chi Square values (χ2 ≥ 25, p ≤ 0.001) from tryptic peptides included KIF12, DISC1, OR8B12, ZC3H12A, TNF, TBC1D8B, GALNT3, EME2, CD1B, BAG1, CPSF2, MMP15, DNAJC2, PHACTR4, OR8B3, GCK, EXOSC7, HMGA1 and NT5C3A among others. Similarly, increased frequency of tryptic phosphopeptides were observed from MOK, SMIM19, NXNL1, SLC24A2, Nbla10317, AHRR, C10orf90, MAEA, SRSF8, TBATA, TNIK, UBE2G1, PDE4C, PCGF2, KIR3DP1, TJP2, CPNE8, and NGF amongst others. STRING analysis showed an increase in cytoplasmic proteins and proteins associated with alternate splicing, exocytosis of luminal proteins, and proteins involved in the regulation of the cell cycle, mitochondrial functions or metabolism and apoptosis. Increases in mean precursor intensity of peptides from common plasma proteins such as DISC1, EXOSC5, UBE2G1, SMIM19, NXNL1, PANO, EIF4G1, KIR3DP1, MED25, MGRN1, OR8B3, MGC24039, POLR1A, SYTL4, RNF111, IREB2, ANKMY2, SGKL, SLC25A5, CHMP3 among others were associated with AD. Tryptic peptides from the highly conserved C-terminus of DISC1 within the sequence MPGGGPQGAPAAAGGGGVSHRAGSRDCLPPAACFR and ARQCGLDSR showed a higher frequency and highest intensity in AD compared to all other disease and controls. Conclusion Proteins apparently expressed in the brain that were directly related to Alzheimer’s including Nerve Growth Factor (NFG), Sphingomyelin Phosphodiesterase, Disrupted in Schizophrenia 1 (DISC1), the cell death regulator retinitis pigmentosa (NXNl1) that governs the loss of nerve cells in the retina and the cell death regulator ZC3H12A showed much higher observation frequency in AD plasma vs the matched control. There was a striking agreement between the proteins known to be mutated or dis-regulated in the brains of AD patients with the proteins observed in the plasma of AD patients from endogenous peptides including NBN, BAG1, NOX1, PDCD5, SGK3, UBE2G1, SMPD3 neuronal proteins associated with synapse function such as KSYTL4, VTI1B and brain specific proteins such as TBATA.

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Section: Discussionmentioning

confidence: 99%

The plasma peptides of Alzheimer’s disease

Florentinus-Mefailoski

Bowden

Scheltens

et al. 2021

Clin Proteom

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“…Amyloid aggregation on the cell membrane results in lipid bilayer disruption and cell leakage, which are potential mechanisms of toxicity 20,21 . Of note, Prkcd was recently identified as a cerebrospinal fluid biomarker related to neurodegeneration induced by beta-amyloid 22 . In addition, we identified 20 genes that were correlated with amyloid deposit patterns and upregulated in GM at 7 months of AD.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal characterization of glial cell activation in an Alzheimer’s disease model by spatially resolved transcriptome

Choi

et al. 2021

Preprint

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The pathophysiological changes that occur with the progression of Alzheimer's disease (AD) are well known, but understanding the spatiotemporal heterogeneity of the brain is needed. Here, we investigated the spatially resolved transcriptome in a 5XFAD AD model of different ages to understand regional changes at the molecular level. We identified early alterations in the white matter (WM) of the AD model before the definite accumulation of amyloid plaques in the gray matter (GM). Changes in the early stage of the disease were involved primarily in glial cell activation in WM, whereas the changes were prominent in the later stage of pathology in GM. We confirmed that disease-associated microglia (DAM) and astrocyte (DAA) signatures also showed initial changes in WM and that activation spreads to GM. Trajectory inference using microglial gene sets revealed the subdivision of DAMs with different spatial patterns. Taken together, these results help to understand the spatiotemporal changes associated with reactive glial cells as a major pathophysiology of AD and provide information for diagnosis and prognosis based on spatiotemporal changes caused by amyloid accumulation in AD.

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“…The ADNI participants were genotyped using several Illumina genotyping platforms. Quality control (QC) procedures for participants and SNPs were performed as described previously [13]. After QC procedures, we selected only non-Hispanic participants of European ancestry and imputed un-genotyped SNPs separately in each platform using Markov Chain Haplotyping with the Haplotype Reference Consortium data as a reference panel [14].…”

Section: Genotypingmentioning

confidence: 99%

BMI1 is associated with CSF amyloid-β and rates of cognitive decline in Alzheimer’s disease

Kim

Bice

et al. 2021

Alz Res Therapy

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Background Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer’s disease (AD). However, the mechanism remains elusive. Based on recent pathophysiological evidence, we sought for the first time to identify genetic variants in BMI1 as associated with AD biomarkers, including amyloid-β. Methods We used genetic, longitudinal cognition, and cerebrospinal fluid (CSF) biomarker data from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort (N = 1565). First, we performed a gene-based association analysis of common single nucleotide polymorphisms (SNPs) (minor allele frequency (MAF) > 5%) located within ± 20 kb of the gene boundary of BMI1, an optimal width for including potential regulatory SNPs in the 5′ and 3′ untranslated regions (UTR) of BMI1, with CSF Aβ1-42 levels. Second, we performed cross-sectional and longitudinal association analyses of SNPs in BMI1 with cognitive performance using linear and mixed-effects models. We replicated association of SNPs in BMI1 with cognitive performance in an independent cohort (N=1084), Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Results Gene-based genetic association analysis showed that BMI1 was significantly associated with CSF Aβ1-42 levels after adjusting for multiple testing using permutation (permutation-corrected p value=0.005). rs17415557 in BMI1 showed the most significant association with CSF Aβ1-42 levels. Participants with minor alleles of rs17415557 have increased CSF Aβ1-42 levels compared to those with no minor alleles. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD. Conclusions Our findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.

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Dysregulated Fc gamma receptor–mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis

Cited by 39 publications

References 78 publications

The plasma peptides of Alzheimer’s disease

The plasma peptides of Alzheimer’s disease

Spatiotemporal characterization of glial cell activation in an Alzheimer’s disease model by spatially resolved transcriptome

BMI1 is associated with CSF amyloid-β and rates of cognitive decline in Alzheimer’s disease

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