Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer's disease

Galea, Elena; Weinstock, Laura D.; Larramona-Arcas, Raquel; Pybus, Alyssa F.; Giménez-Llort, Lydia; Escartin, Carole; Wood, Levi B.

doi:10.1016/j.nbd.2022.105655

Cited by 52 publications

(39 citation statements)

References 55 publications

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“…Taken together, these findings reinforce the idea that AD-associated reactive astrogliosis tracks with the spatiotemporal progression of AD, highlighting a severe end-stage dysfunctional or maladaptive response of astrocytes likely caused by their chronic exposure to A β , pTau, and ongoing neurodegeneration 24 .…”

Section: Discussionsupporting

confidence: 76%

“…The latter result also suggests that astrocytes undergo an energy failure as a result of the chronic exposure to both A β and pTau. Notably, prior bulk transcriptomic analyses have highlighted energy metabolism deficits as a feature of AD and other neurodegenerative diseases 23 but have either attributed this finding to the severe neuronal dysfunction and loss or imputed it to astrocytes only through indirect computational methods 24 . Our data seem to confirm that astrocytes, and not only neurons, suffer mitochondrial dysfunction and energy deficits that contribute to these observed bulk RNA changes.…”

Section: Discussionmentioning

confidence: 99%

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Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Serrano-Pozo

Woodbury

et al. 2022

Preprint

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Astrocytes play a critical role in brain homeostasis and normal functions but their changes along the spatiotemporal progression of Alzheimer's disease (AD) neuropathology remain largely unknown. Here we performed single-nucleus RNA-sequencing on brain regions along the stereotypical progression of AD pathology from donors ranging the entire normal aging-AD continuum comprising 628,943 astrocyte nuclei from 32 donors across 5 brain regions. We discovered temporal gene-expression-trajectories with gene sets differentially activated at various disease stages. Surprisingly, a gene set enriched in proteostasis and energy metabolism, was upregulated in late-stage but unexpectedly returned to baseline levels in end-stage, suggesting exhaustion of response in "burnt-out" astrocytes. The spatial gene-expression-trajectories revealed that astrocytic genes of tripartite synapses are dysregulated in parallel to the stereotypical progression of tangle pathology across regions. We identified astrocyte heterogeneity across brain regions with a continuum from homeostatic to reactive cells through "intermediate" transitional states. These findings suggest complex astrocytic dysfunction in AD neurodegeneration.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Serrano-Pozo

Woodbury

et al. 2022

Preprint

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“…To put our results in context with human data, we compared the list of proteins that we generated with the astrocyte-specific genes that were found to be differentially expressed in early-vs late-stage human AD brain (Mathys et al 2019), in AD vs control brain (Grubman et al 2019; Lau et al 2020; Sadick et al 2022) and showing a positive correlation with Aß or phospho-tau pathology (Smith et al 2021). We also included a comparison with a study where astrocyte-specific gene clusters were applied to 766 whole brain transcriptomes, including control, mild cognitive impairment (MCI) and demented (AD) cases (Galea et al 2022) (Supplementary Table 9). After selecting those genes that encode proteins predicted to be secreted, we searched for those that were differentially regulated by Aβ in our study (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aß

Matafora

Gorb

Noble

et al. 2023

Preprint

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Astrocytes associate with amyloid plaques in Alzheimer's disease (AD). Astrocytes react to changes in the brain environment, including to increasing concentrations of amyloid-beta (A beta).However, the precise response of astrocytes to soluble small Abeta oligomers at concentrations similar to those present in the human brain has not been addressed. In this study, we exposed astrocytes to neuronal media containing soluble human Abeta oligomers and used proteomics to investigate changes in the astrocyte secretome. Our data shows dysregulated secretion of astrocytic proteins involved in the extracellular matrix and cytoskeletal organization and increase secretion of proteins involved in oxidative stress responses and those with chaperone activity. Several of these proteins have been identified in previous transcriptomic and proteomic studies using brain tissue from human AD and cerebrospinal fluid (CSF). Our work highlights the relevance of studying astrocyte secretion to understand the brain response to AD pathology and the potential use of these proteins as biomarkers for the disease.

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“…Mitochondrial dysfunction in astrocytes has been proposed to contribute to oxidative stress in AD, based on transcriptomic analyses of astrocytes in mouse models of AD and samples from patients (Abramov et al, 2004; Galea et al, 2022; Orre et al, 2014). Furthermore, ultra‐deep proteomic analysis of cerebrospinal fluid (CSF) from patients with AD indicates that a large proportion of the dysregulated proteins are mitochondrial (Wang et al, 2020), many of them being highly abundant or mainly present in astrocytes (see http://www.brainrnaseq.org/).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of UCP4 in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer's disease

Rosenberg

Reva

Binda

et al. 2022

Glia

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Alzheimer's disease (AD) is becoming increasingly prevalent worldwide. It represents one of the greatest medical challenges as no pharmacologic treatments are available to prevent disease progression. Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early-stage AD is associated with hypometabolism and oxidative stress. Contrary to neurons that are vulnerable to oxidative

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Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer's disease

Cited by 52 publications

References 55 publications

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Proteomics of the astrocyte secretome reveals changes in their response to soluble oligomeric Aß

Overexpression of UCP4 in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer's disease

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