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Cited by 83Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Galea, Elena, Weinstock, Laura D., Larramona-Arcas, Raquel, Pybus, Alyssa F., Giménez-Llort, Lydia, Escartin, Carole, Wood, Levi B.·2022·Neurobiology of Disease
DOI 10.1016/j.nbd.2022.105655PMC PMC9504227

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Abstract

The phenotypic transformation of astrocytes in Alzheimer's disease (AD) is still not well understood. Recent analyses based on single-nucleus RNA sequencing of postmortem Alzheimer's disease (AD) samples are limited by the low number of sequenced astrocytes, small cohort sizes, and low number of differentially expressed genes detected. To optimize the detection of astrocytic genes, we employed a novel strategy consisting of the localization of pre-determined astrocyte and neuronal gene clusters in publicly available whole-brain transcriptomes. Specifically, we used cortical transcriptomes from 766 individuals, including cognitively normal subjects (Controls), and people diagnosed with mild cognitive impairment (MCI) or dementia due to AD. Samples came from three independent cohorts organized by the Mount Sinai Hospital, the Mayo Clinic, and the Religious Order Study/Memory and Aging Project (ROSMAP). Astrocyte- and neuron-specific gene clusters were generated from human brain cell-type specific RNAseq data using hierarchical clustering and cell-type enrichment scoring. Genes from each cluster were manually annotated according to cell-type specific functional Categories. Gene Set Variation Analysis (GSVA) and Principal Component Analysis (PCA) were used to establish changes in these functional categories among clinical cohorts. We highlight three novel findings of the study. First, individuals with the same clinical diagnosis were molecularly heterogeneous. Particularly in the Mayo Clinic and ROSMAP cohorts, over 50% of Controls presented down-regulation of genes encoding synaptic proteins typical of AD, whereas 30% of patients diagnosed with dementia due to AD presented Control-like transcriptomic profiles. Second, down-regulation of neuronal genes related to synaptic proteins coincided, in astrocytes, with up-regulation of genes related to perisynaptic astrocytic processes (PAP) and down-regulation of genes encoding endolysosomal and mitochondrial proteins. Third, down-regulation of astrocytic mitochondrial genes inversely correlated with the disease stages defined by Braak and CERAD scoring. Finally, we interpreted these changes as maladaptive or adaptive from the point of view of astrocyte biology in a model of the phenotypical transformation of astrocytes in AD. The main prediction is that early malfunction of the astrocytic endolysosomal system, associated with progressive mitochondrial dysfunction, contribute to Alzheimer's disease. If this prediction is correct, therapies preventing organelle dysfunction in astrocytes may be beneficial in preclinical and clinical AD.

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  • There is a severe end-stage dysfunctional or maladaptive response of astrocytes likely caused by their chronic exposure to Aβ, pTau and ongoing neurodegeneration.

    “highlighting a severe end-stage dysfunctional or maladaptive response of astrocytes likely caused by their chronic exposure to Aβ, pTau and ongoing neurodegeneration52”

    From Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease (2024) · cites this paper as [52]

    In the Discussion’s model of cortical astrocyte transformation (page unavailable), the paper predicts that astrocytes become globally malfunctional in advanced Alzheimer’s disease and proposes amyloid-β as a driver of their phenotypic change. It does not attribute that late-stage dysfunction specifically to chronic exposure to pTau or ongoing neurodegeneration, so the proposed combination of causes is only partly supported. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of Alzheimer's disease.

    “Mitochondrial damage in astrocytes can lead to the accumulation of lipid droplets, thereby further exacerbating the pathological progression of AD [16, 17, 18].”

    From Aerobic exercise improves astrocyte mitochondrial quality and transfer to neurons in a mouse model of Alzheimer's disease (2025) · cites this paper as [16]

    The Discussion (Key implications and predictions; page unavailable) describes mitochondrial dysfunction in AD astrocytes. The Discussion’s model of astrocyte transformation predicts that this dysfunction contributes to AD progression, but neither passage links mitochondrial damage to lipid-droplet accumulation or identifies lipid droplets as a cause of worsening disease. Searches for lipid droplets and lipid accumulation found no such link in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Galea, E., Weinstock, L. D., Larramona-Arcas, R., Pybus, A. F., Giménez-Llort, L., Escartin, C., & Wood, L. B.
Affiliations
  • Institució Catalana de Recerca i Estudis Avançats (ES)
  • Georgia Institute of Technology (US)
  • Centre National de la Recherche Scientifique (FR)
Corresponding author
  • Galea, Elena
  • Wood, Levi B.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2022-05
Volume
166
Pages
105655
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2022.105655
PMC
PMC9504227
OpenAlex
W4210871348
Cited by
83
References
10
Citations by year
2026: 13 · 2025: 12 · 2024: 30 · 2023: 15 · 2022: 13
FWCI
11.15
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion, cc-by-nc-nd)
  • medRxiv (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (R01 NS080820, U24 NS072026)
  • National Institutes of Health (T32-GM008433)
  • Mayo Clinic
  • Centre National de la Recherche Scientifique
  • Mayo Foundation for Medical Education and Research
  • Arizona Department of Health Services (211002)
  • Fundació la Marató de TV3 (201414-30)
  • Michael J. Fox Foundation for Parkinson's Research (R01AG30146, P30AG10161, R01AG15819, R01AG36042, R01AG17917)
  • Coins for Alzheimer's Research Trust
  • National Institute on Aging (P30 AG19610, R01 AG018023, R01 AG003949, U01 AG006786, P50 AG016574, R01 AG025711, R01 AG032990, U01 AG006576, R01 AG017216, U01 AG046139)
  • Commissariat à l'Énergie Atomique et aux Énergies Alternatives
  • Generalitat de Catalunya
  • Arizona Biomedical Research Commission (1001, 0011, 05-901, 4001)
  • Illinois Department of Public Health
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, astrocytes, mitochondrial dysfunction, endolysosomal dysfunction, mild cognitive impairment, cortical transcriptome, transcriptomic heterogeneity
MeSH terms
Alzheimer Disease, Astrocytes, Humans, Organelles, Gene Expression Profiling, Transcriptome, Cognitive Dysfunction

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