Age-Associated Molecular Changes in Human Hippocampus Subfields as Determined by Quantitative Proteomics

Mol, Praseeda; Chatterjee, Oishi; Gopalakrishnan, Lathika; Mangalaparthi, Kiran K.; Bhat, Firdous Ahmad; Kumar, Manish; Nair, Bipin G.; Shankar, Susarla Krishna; Mahadevan, Anita; Prasad, T. S. Keshava

doi:10.1089/omi.2022.0053

Cited by 5 publications

(10 citation statements)

References 59 publications

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“…A recent study of frontal cortex proteins affected by ageing and AD [18] did not report data on TMEM106B but showed the same highly signi cant positive and negative correlations with age for ASAH1 and CORO1A, respectively. Our observation of a general increase in electron transport chain proteins with age is in agreement with published studies on the rat hippocampus [16], but contrasts with other studies reporting either no signi cant change in mitochondrial proteins [18] or decreased levels of electron transport chain proteins in the hippocampus of humans aged > 90 years, compared to those aged 20 to 49 years [14,17]. Similarly, while our study demonstrated an overall increase in abundance for ribosomal protein subunits with increasing age, prior studies have reported dissonant ndings regarding changes to ribosomal protein abundance across humans, mice, monkeys, and sh [11,15,18,57].…”

Section: Discussionsupporting

confidence: 87%

“…The majority of proteins whose levels were signi cantly correlated with age were involved in constitutive metabolic and cellular processes such as lipid and amino acid metabolism, translation, and control of cell adhesion and the cytoskeleton. Increased levels of the lysosomal proteins TMEM106B and ASAH1 (acid ceramidase) concur with prior studies demonstrating increased abundance of lysosomal proteins with ageing in human brains [14,18], as well as increased lifetimes for lysosomal proteins in old compared to young adult mice [10]. A recent study of frontal cortex proteins affected by ageing and AD [18] did not report data on TMEM106B but showed the same highly signi cant positive and negative correlations with age for ASAH1 and CORO1A, respectively.…”

Section: Discussionsupporting

confidence: 85%

“…This allowed us to identify age-dependent changes to the proteome across the age range that is most relevant to the onset of dementia. We also note that sample sizes in prior studies with human hippocampus were limited to 3 or 4 samples per group [14,17]. An important limitation of our study is that overrepresentation of ribosomal and electron transport chain subunits may re ect the natural bias of proteomics towards more abundant proteins.…”

Section: Discussionmentioning

confidence: 96%

“…While there have been many studies characterizing transcriptomic changes in the ageing human brain [12,13], few have investigated proteomic changes. Proteomic analyses of the rat, monkey, and human hippocampus reported changes to electron transport proteins [14][15][16][17], lysosomal proteins [14], redox control [15,16], RNA splicing [14], and ribosomal stoichiometry [15] with increased age. However, the existing proteomic datasets for normal ageing in the human hippocampus are limited by small sample sizes [14,17].…”

mentioning

confidence: 99%

“…Proteomic analyses of the rat, monkey, and human hippocampus reported changes to electron transport proteins [14][15][16][17], lysosomal proteins [14], redox control [15,16], RNA splicing [14], and ribosomal stoichiometry [15] with increased age. However, the existing proteomic datasets for normal ageing in the human hippocampus are limited by small sample sizes [14,17]. A recent, larger proteomic analysis of human frontal cortex demonstrated downregulation of mitochondrial and synaptic proteins in AD cases, whereas only synaptic proteins were inversely correlated with physiological ageing (ages 30 to 69) [18].…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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Transcriptomic profiling of nuclei from paraformaldehyde-fixed and formalin-fixed paraffin-embedded brain tissues

Guo,

Ma,

et al. 2023

Analytica Chimica Acta

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Transcriptomic profiling of nuclei from PFA-fixed and FFPE brain tissues

Guo

Ma²,

Dang

et al. 2023

Preprint

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Formalin-fixed and paraffin-embedded (FFPE) tissue archives are the largest repository of clinically annotated specimens, and FFPE-compatible single cell gene expression workflow had been developed and applied recently. However, for tissues where cells are hard to dissociate or brains with complex neuronal cells, nuclear transcriptomic profiling are desirable. Moreover, the effects of standard pathological practice on the transcriptome of samples obtained from such archived specimens was also largely anecdotal. Here, we performed RNA-seq of nuclei from hippocampal of mice that underwent freezing, paraformaldehyde (PFA) fixation, and paraffin embedding. Then, we comprehensively evaluated the parameters affecting mRNA quality, transcription patterns, functional level and cell states of nuclei, including PFA fixation time and storage time of FFPE tissues. The results showed that the transcriptome signatures of nuclei isolated from fresh PFA-fixed and fresh FFPE tissues were more similar to matched frozen samples. By contrast, the brain fixed for more than 3 days had prominent impacts on the sequencing data, such as the numbers and biotypes of gene, GC content and ratio of reads interval. Commensurately, prolonged fixation time will result in more differentially expressed genes, especially those enriched in spliceosome and synaptic related pathways, affecting the analysis of gene splicing and neuron cells. MuSiC deconvolution results revealed that PFA infiltrating brains for 3 days will destroy the real cell states, and the proportion of neuron, endothelial and oligodendrocytes diminished while that of microglia was reversed. Yet the effect of storage time on cell composition was more neglectable for FFPE samples. In addition, oligodendrocyte precursor cells were most affected in all fixed samples, and their destruction was independent of fixation time and preservation time. The comprehensive results highlighted that fixation time had much more influences on the nuclear transcriptomic profiles than FFPE retention time, and the cliff-like effects appeared to occur over a fixed period of 1-3 days, with no more differences from additional fixation durations.

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Age-Associated Molecular Changes in Human Hippocampus Subfields as Determined by Quantitative Proteomics

Cited by 5 publications

References 59 publications

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

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

Transcriptomic profiling of nuclei from paraformaldehyde-fixed and formalin-fixed paraffin-embedded brain tissues

Transcriptomic profiling of nuclei from PFA-fixed and FFPE brain tissues

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