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Cited by 46Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease

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Das, Sudeshna, Li, Zhaozhi, Wachter, Astrid, Alla, Srinija, Noori, Ayush, Abdourahman, Aicha, Tamm, Joseph A., Woodbury, Maya E. +5 more·2024·Alzheimer's & Dementia
DOI 10.1002/alz.13387PMC PMC10792109
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Abstract

INTRODUCTION: Omics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer's disease (AD) but the spatial relationships with plaques and tangles and APOE ‐linked differences remain unclear. METHODS: We performed laser capture microdissection of amyloid beta (Aβ) plaques, the 50 μm halo around them, tangles with the 50 μm halo around them, and areas distant (> 50 μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA‐sequencing. RESULTS: Aβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque > peri‐plaque > tangle > distant for these changes. AD APOE ε 4 homozygotes had greater changes than APOE ε 3 across locations, especially within Aβ plaques. DISCUSSION: Transcriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by the APOE ε 4 allele.

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  • The disease-associated microglial (DAM) response is differentially regulated by the various APOE isoforms, probably through their differential binding to specific surface microglial receptors such as TREM2.

    “This so-called disease-associated microglial (DAM) response is differentially regulated by the various APOE isoforms, probably through their differential binding to specific surface microglial receptors such as TREM2 (refs. 152,153)”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [153]

    The Results and Discussion (page unavailable) show that APOE ε4, compared with ε3, augments plaque-associated microglial gene expression, including TREM2; the Results also find the DAM signature enriched in plaques. The paper does not establish that differential binding of APOE isoforms to TREM2 or other microglial receptors explains this effect. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • The APOE-TREM2 axis has been found in transcriptomic post-mortem analyses of human brains, with APOEε4 carriers exhibiting a more prominent pro-inflammatory and phagocytic microglial transcriptomic signature.

    “this APOE–TREM2 axis has also been found in transcriptomic post-mortem analyses of human brains, with APOEε4 carriers exhibiting a more prominent pro-inflammatory and phagocytic microglial transcriptomic signature152,153.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [153]

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Authors
Das, S., Li, Z., Wachter, A., Alla, S., Noori, A., Abdourahman, A., Tamm, J. A., Woodbury, M. E., Talanian, R. V., Biber, K., Karran, E. H., Hyman, B. T., & Serrano‐Pozo, A.
Affiliations
  • Harvard University (US)
  • Massachusetts General Hospital (US)
  • AbbVie (Germany) (DE)
  • AbbVie (United States) (US)
Corresponding author
Serrano‐Pozo, Alberto
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2023-07-17
Volume
20
Issue
1
Pages
74-90
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.13387
PMC
PMC10792109
OpenAlex
W4384625954
Cited by
46
References
24
Citations by year
2026: 8 · 2025: 21 · 2024: 14 · 2023: 3
FWCI
8.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
Alzheimer's Association (AACF‐17‐524184, AACF‐17‐524184‐RAPID)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, amyloid plaques

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