Defective Lysosomal Lipid Catabolism as a Common Pathogenic Mechanism for Dementia

Lee, Jun Yup; Marian, Oana C.; Don, Anthony S.

doi:10.1007/s12017-021-08644-4

Cited by 11 publications

(8 citation statements)

References 281 publications

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“…The module includes the C1q complement factors that have consistently been associated with Trem2 expression in Alzheimer’s mouse models (Matarin et al ., 2015). However, the other genes are associated with the phagosome (Plek) (Brumell et al, 1999) or lysosomal function( Ctsz, Ctss, and Grn) (Infante et al, 2008; Lee et al, 2021a; Paushter et al, 2018; Tjondrokoesoemo et al, 2016). All of these genes are linked with the dependence on the Trem2 genotype suggesting that Trem2 WT is the essential controller.…”

Section: Discussionmentioning

confidence: 99%

Upregulation ofTrem2expression occurs exclusively on microglial contact with plaques

Wood

Wong

Joghee

et al. 2022

Preprint

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Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia touching plaques, neighboring plaques, and far from plaques in 18-month-old APPNLF/NLF knock-in mice with and without the Alzheimer's disease risk mutation Trem2R47H/R47H. We report that, in AppNLF/NLF mice, expression of 35/55 PIGs, is exclusively upregulated in microglia that are touching plaques. In 7 PIGs including Trem2 this upregulation is prevented by the Trem2R47H/R47H mutation. Unlike in young mice, knock-in of the Trem2R47H/R47H mutation does not significantly decrease the Trem2 expression but decreases protein levels by 20% in the absence of plaques. On plaques, despite the mutation preventing increased gene expression, TREM2 protein levels increased by 1.6-fold (compared to 3-fold with Trem2WT/WT) and microglial density increased 20-fold compared to 30-fold. Hence microglia must touch plaques before Trem2 gene expression is increased but small changes in protein expression can increase microglia density without a change in gene expression.

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Section: Discussionmentioning

confidence: 99%

Upregulation ofTrem2expression occurs exclusively on microglial contact with plaques

Wood

Wong

Joghee

et al. 2022

Preprint

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“…Given that (i) many of the most important gene variants affecting dementia risk regulate lipid transport and catabolism [53], (ii) structural modelling has proposed a lipid binding function for TMEM106B [54], and (iii) TMEM106B protein levels were correlated with proteins regulating fatty acid and lipid metabolism, we used lipidomic analysis to determine how dementia risk allele rs1990622-A affects lipid composition in the hippocampus of cognitively normal humans. A total of 234 phospholipids, sphingolipids, and neutral lipids were quanti ed by LC-MS/MS.…”

Section: Myelin Lipid Content Is Decreased In Carriers Of the Rs19906...mentioning

confidence: 99%

“…A total of 234 phospholipids, sphingolipids, and neutral lipids were quanti ed by LC-MS/MS. As variants in APOE, which encodes a lipid transport protein, are the most signi cant determinant of genetic risk for dementia [53], we rst determined whether lipid levels were signi cantly affected by APOE genotype. In one-way ANOVA comparing 46 cases with a risk-neutral APOE e3/e3 genotype, 12 with a protective e3/e2 or e2/e2 genotype (e2 carriers), and 12 with a risk-increasing e3/e4 genotype, no lipids were signi cantly regulated (Q < 0.05) at the level of individual lipid species or lipid class totals (Supplementary Tables 4 and 5).…”

Section: Myelin Lipid Content Is Decreased In Carriers Of the Rs19906...mentioning

confidence: 99%

The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus

Lee

Harney

Larance

et al. 2023

Preprint

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Background The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. Methods Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66–104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. Results Forty proteins were associated with age at false discovery rate-corrected P < 0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. Transmembrane protein 106B (TMEM106B), a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with age was specific to carriers of the rs1990622-A allele in the TMEM106B gene that is associated with increased risk for frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and hippocampal sclerosis with ageing. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype. Conclusions Our study provides the first evidence that TMEM106B protein abundance is increased with brain ageing in humans, and the first evidence that the major TMEM106B dementia risk allele affects brain lipid homeostasis, with a clear effect on myelin lipid content. Our data implies that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.

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“…A recent study by Shoyaib et al has shown no substantial effect of Panobinostat (pan-HDACs inhibitors) or Entinostat (inhibitors of HDAC1/HDAC3) on motor recovery in mice after photothrombotic stroke. This was accompanied by negligible changes of parvalbumin-positive neurons and comparable infarct volumes among experimental groups, while a dose-dependent increase in acetylated histone 3 was observed in the peri-infarct cortex of drug-treated animals [ 19 ].…”

Section: Histone Deacetylasesmentioning

confidence: 99%

The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses

Demyanenko

Sharifulina

2021

IJMS

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Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors and signaling proteins involved in the regulation of survival and death in cerebral ischemia.

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Defective Lysosomal Lipid Catabolism as a Common Pathogenic Mechanism for Dementia

Cited by 11 publications

References 281 publications

Upregulation ofTrem2expression occurs exclusively on microglial contact with plaques

Upregulation ofTrem2expression occurs exclusively on microglial contact with plaques

The major TMEM106B dementia risk allele affects TMEM106B protein levels and myelin lipid homeostasis in the ageing human hippocampus

The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses

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