Compilation of reported protein changes in the brain in Alzheimer’s disease

Askenazi, Manor; Kavanagh, Tomas; Pires, Geoffrey; Ueberheide, Beatrix; Wısnıewskı, Thomas; Drummond, Eleanor

doi:10.1038/s41467-023-40208-x

Cited by 25 publications

(17 citation statements)

References 78 publications

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“…More specifically, high factor WM_F1 scores were characterised by a pan-glial upregulation of genes involved with protein folding, chaperone proteins and ubiquitination e.g. HSPB1, HSPA4L, HSP90AA, BAG3, SERPINH1 (as found in other neurodegenerative diseases 34,35 ), and reduced microglial expression of CX3CR1, P2RY12 and P2RY13 (homeostatic markers), suggesting an adaptive cellular response to stress (Fig. 3c, Extended Data Fig.…”

Section: Coordinated Multicellular Gene Expression Programs Define Pa...mentioning

confidence: 89%

Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

Macnair

Calini

Agirre

et al. 2022

Preprint

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The lack of understanding as to the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies and biomarkers. Here, to address this gap, we analysed 740,000 single nuclei RNAseq profiles of 165 samples of white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 55 MS patients and 28 controls. We find that gene expression changes in response to MS are highly cell-type specific in WM and GM lesions but are largely shared within an individual cell-type across lesions, following a continuum rather than discrete lesion-specific molecular programs. The major biological determinants of variability in gene expression in MS samples relate to individual patient effects, rather than to lesion types or other metadata. Using multi-omics factor analysis (MOFA+), we identify three subgroups of MS patients with distinct oligodendrocyte composition and WM glial gene expression signatures, suggestive of engagement of different pathological/regenerative processes. The discovery of these three patterns significantly advances our mechanistic understanding of progressive MS, provides a framework to use molecular biomarkers to stratify patients for best therapeutic approaches for progressive MS, and highlights the need for precision-medicine approaches to address heterogeneity among MS patients.

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Section: Coordinated Multicellular Gene Expression Programs Define Pa...mentioning

confidence: 89%

Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

Macnair

Calini

Agirre

et al. 2022

Preprint

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“…5, A and B, and table S6, A and B), some important glycoform changes may have been missed as a result of excluding intact glycopeptides with missing values in >50% of the samples in our analyses. Furthermore, the relatively small sample size used in this study only allowed detection of disease-associated glycosylation changes with a large effect size, and more subtle changes may have been missed ( 83 ). Despite these limitations, we anticipate that the methodologies and findings presented here will facilitate further studies of disease-associated glycoforms and site-specific glycan changes in AD.…”

Section: Discussionmentioning

confidence: 99%

Human brain glycoform coregulation network and glycan modification alterations in Alzheimer’s disease

Zhang,

Ma,

Chin

et al. 2024

Sci. Adv.

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Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer’s disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain glycoproteome into networks of coregulated glycoforms and glycans and discovered glycoform and glycan modules associated with AD clinical phenotype, amyloid-β accumulation, and tau pathology. Our findings provide valuable insights into disease pathogenesis and a rich resource of glycoform and glycan changes in AD and pave the way forward for developing glycosylation-based therapies and biomarkers for AD.

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“…A number of Tmed proteins are dysregulated in mild cognitive impairment (MCI) or AD brains: While TMED5 expression increases in the AD parietal cortex, 102 expression of both TMED4 and TMED9 decreases in the AD frontal cortex. 103–105 Tmed proteins regulate processing of secretory proteins, and have been primarily studied in the context of coatomer (COP) cargo selection and vesicle formation. However, Tmed proteins also have roles in later secretory compartments.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction

Krogsaeter,

McKetney,

Marquez

et al. 2023

Preprint

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SummaryApoE4 is the primary risk factor for Alzheimer’s Disease. While apoE is primarily expressed by astrocytes, AD pathology including endosomal abnormalities and mitochondrial dysfunction first occurs in neurons. Lysosomes are poised at the convergence point between these features. We find that apoE4-expressing cells exhibit lysosomal alkalinization, reduced lysosomal proteolysis, and impaired mitophagy. To identify driving factors for this lysosomal dysfunction, we performed quantitative lysosomal proteome profiling. This revealed that apoE4 expression results in lysosomal depletion of Lgals3bp and accumulation of Tmed5 in both Neuro-2a cells and postmitotic human neurons. Modulating the expression of both proteins affected lysosomal function, with Tmed5 knockdown rescuing lysosomal alkalinization in apoE4 cells, and Lgals3bp knockdown causing lysosomal alkalinization and reduced lysosomal density in apoE3 cells. Taken together, our work reveals that apoE4 exerts gain-of-toxicity by alkalinizing the lysosomal lumen, pinpointing lysosomal Tmed5 accumulation and Lgals3bp depletion as apoE4-associated drivers for this phenotype.

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Compilation of reported protein changes in the brain in Alzheimer’s disease

Cited by 25 publications

References 78 publications

Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

Human brain glycoform coregulation network and glycan modification alterations in Alzheimer’s disease

Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction

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