TREM2‐induced activation of microglia contributes to synaptic integrity in cognitively intact aged individuals with Alzheimer's neuropathology
Open accessAbstract
The existence of individuals who remain cognitively intact despite presenting histopathological signs of Alzheimer's disease (AD), here referred to as “Nondemented with AD neuropathology” (NDAN), suggests that some mechanisms are triggered to resist cognitive impairment. Exposed phosphatidylserine (ePS) represents a neuronal “eat‐me” signal involved in microglial‐mediated phagocytosis of damaged synapses. A possible mediator of this process is TREM2, a microglial surface receptor activated by ligands including PS. Based on TREM2 role in the scavenging function of microglia, we hypothesize that an efficient microglial phagocytosis of damaged synapses underlies synaptic resilience in NDAN, thus protecting from memory deficits. Using immunofluorescence microscopy, we performed a comparative study of human post‐mortem frontal cortices of aged‐matched, AD and NDAN individuals. We studied the distribution of activated microglia (IBA1, IBA1+/CD68+ cells) and phagocytic microglia‐related proteins (TREM2, DAP12), demonstrating higher microglial activation and TREM2 expression in NDAN versus AD. A study of the preservation of synapses around plaques, assessed using MAP2 and βIII tubulin as dendritic and axonal markers, respectively, and PSD95 as a postsynaptic marker, revealed preserved axonal/dendritic structure around plaques in NDAN versus AD. Moreover, high levels of PSD95 around NDAN plaques and the colocalization of PSD95 with CD68 indicated a prompt removal of damaged synapses by phagocytic microglia. Furthermore, Annexin V assay on aged‐matched, AD and NDAN individuals synaptosomes revealed increased levels of ePS in NDAN, confirming damaged synapses engulfment. Our results suggest a higher efficiency of TREM2‐induced phagocytic microglia in removing damaged synapses, underlying synaptic resilience in NDAN individuals.
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Higher levels of the microglial phagocytic complex TREM2/DAP12 are present in Aβ amyloid plaques in NDAN than in AD.
“The authors also reported higher levels of the microglial phagocytic complex TREM2/DAP12 in Aβ amyloid plaques in NDAN than in those in AD,”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [27]
The Results report more TREM2-positive microglia around Aβ plaques in NDAN than in AD (Figure 1), and greater TREM2–DAP12 colocalization in NDAN frontal cortex (Figure 3). They do not specifically show higher levels of the TREM2/DAP12 complex in the plaques; the complex was assessed across frontal cortex, while the plaque-localized analysis measured TREM2. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBrains of AsymAD cases exhibit significant upregulation of phagocytic microglia.
“Additionally, the brains of AsymAD cases exhibit significant upregulation of phagocytic microglia, which help remove damaged synapses as a protective mechanism [27].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [27]
Phagocytic microglia help remove damaged synapses as a protective mechanism.
“Additionally, the brains of AsymAD cases exhibit significant upregulation of phagocytic microglia, which help remove damaged synapses as a protective mechanism [27].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [27]
A high abundance of activated microglia is present in the cortices of an NDAN patient cohort.
“Moreover, a recent study revealed a high abundance of activated microglia in the cortices of an NDAN patient cohort.”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [27]
Microglia surrounding Aβ plaques in NDAN are hyperactive and more effectively recognize damaged synapses with greater phagocytic capacity than microglia in AD.
“concluding that microglia surrounding Aβ plaques in NDAN are hyperactive and more effectively recognize damaged synapses with greater phagocytic capacity than microglia in AD [27].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [27]
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“combination with IBA1 and CD68 (Figure 4A–C), the latter considered as a microglial lysosomal and activated microglia marker [28].”
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“Although our data support previous evidence suggesting that endocytosis and phagocytosis might underlie synaptic resilience in AsymAD individuals [27, 92], the literature also indicates the role of some of these DEGs in actin-based motility (pink highlighted genes in Fig.”
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- Authors
- Fracassi, A., Marcatti, M., Tumurbaatar, B., Woltjer, R., Moreno, S., & Taglialatela, G.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Oregon Health & Science University (US)
- Roma Tre University (IT)
- Corresponding author
- Taglialatela, Giulio
- Venue
- Brain Pathology
- Publisher
- Wiley
- Published
- 2022-07-11
- Volume
- 33
- Issue
- 1
- Pages
- e13108-e13108
- ISSN
- 1015-6305 (ISSN-L)
- 1750-3639
- PMC
- PMC9836373
- OpenAlex
- W4285012943
- Cited by
- 92
- References
- 14
- Citations by year
- 2026: 20 · 2025: 22 · 2024: 35 · 2023: 13 · 2022: 2
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain Pathology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Iris (Roma Tre University) (submittedVersion)
- Funders
- National Institute on Aging (R01AG060718, R01AG069433, P30AG008017)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, microglial activation, microglial phagocytosis, synaptic integrity, Alzheimer's disease, phosphatidylserine, amyloid plaques, PSD-95, DAP12
- MeSH terms
- Aged, Alzheimer Disease, Humans, Macrophages, Membrane Glycoproteins, Receptors, Immunologic, Synapses, Microglia, Plaque, Amyloid, Cognitive Dysfunction
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