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Cited by 17Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Untangling Tau: Molecular Insights into Neuroinflammation, Pathophysiology, and Emerging Immunotherapies

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Davidson, Ryder, Krider, Reese I., Borsellino, Philip, Noorda, Keith, Alhwayek, George, Vida, Thomas A.·2023·Current Issues in Molecular Biology
DOI 10.3390/cimb45110553PMC PMC10670294
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Abstract

Neuroinflammation, a core pathological feature observed in several neurodegenerative diseases, including Alzheimer’s disease (AD), is rapidly gaining attention as a target in understanding the molecular underpinnings of these disorders. Glial cells, endothelial cells, peripheral immune cells, and astrocytes produce a variety of pro-inflammatory mediators that exacerbate the disease progression. Additionally, microglial cells play a complex role in AD, facilitating the clearance of pathological amyloid-beta peptide (Aβ) plaques and aggregates of the tau protein. Tau proteins, traditionally associated with microtubule stabilization, have come under intense scrutiny for their perturbed roles in neurodegenerative conditions. In this narrative review, we focus on recent advances from molecular insights that have revealed aberrant tau post-translational modifications, such as phosphorylation and acetylation, serving as pathological hallmarks. These modifications also trigger the activation of CNS-resident immune cells, such as microglia and astrocytes substantially contributing to neuroinflammation. This intricate relationship between tau pathologies and neuroinflammation fosters a cascading impact on neural pathophysiology. Furthermore, understanding the molecular mechanisms underpinning tau’s influence on neuroinflammation presents a frontier for the development of innovative immunotherapies. Neurodegenerative diseases have been relatively intractable to conventional pharmacology using small molecules. We further comprehensively document the many alternative approaches using immunotherapy targeting tau pathological epitopes and structures with a wide array of antibodies. Clinical trials are discussed using these therapeutic approaches, which have both promising and disappointing outcomes. Future directions for tau immunotherapies may include combining treatments with Aβ immunotherapy, which may result in more significant clinical outcomes for neurodegenerative diseases.

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  • Neuroinflammation exacerbates tau pathology, as activated microglia and astrocytes release cytokines that modulate kinase activity and impair clearance mechanisms.

    “Neuroinflammation also exacerbates tau pathology, as activated microglia and astrocytes release cytokines that modulate kinase activity and impair clearance mechanisms [51].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [51]

    Section 2 describes sustained cytokine release from activated glial cells, reduced clearance after prolonged microglial activation, tau aggregate propagation, and a possible contribution of astrocytes to tau hyperphosphorylation. Section 3.1 identifies kinases involved in tau phosphorylation, but the copy does not link cytokine release to altered kinase activity or establish that cytokines impair clearance. Page numbers were not provided. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Tau pathology promotes inflammatory signaling, creating a feed-forward loop.

    “In turn, tau pathology promotes inflammatory signaling, creating a feed-forward loop.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [51]

  • MAMs house γ-secretase complexes containing presenilin-1 and -2, positioning them as key sites for APP processing.

    “MAMs also house γ-secretase complexes containing presenilin-1 and −2, positioning them as key sites for APP processing [51].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [51]

    The Introduction mentions APP and presenilin (PSEN1/2) only as genes associated with early-onset Alzheimer’s disease. Searches for MAMs, mitochondria-associated membranes, and γ-secretase found no passage about their location or role in APP processing; the cited paper therefore does not establish the attributed claim. (LLM, conf=0.77)

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Cited by

Sorted by citations

Authors
Davidson, R., Krider, R. I., Borsellino, P., Noorda, K., Alhwayek, G., & Vida, T. A.
Affiliations
University of Nevada, Las Vegas (US)
Corresponding author
Vida, Thomas A.
ORCID
Venue
Current Issues in Molecular Biology
Publisher
MDPI AG
Published
2023-11-02
Volume
45
Issue
11
Pages
8816-8839
ISSN
  • 1467-3037 (ISSN-L)
  • 1467-3045
DOI
10.3390/cimb45110553
PMC
PMC10670294
OpenAlex
W4388221191
Cited by
17
References
32
Citations by year
2026: 4 · 2025: 9 · 2024: 4
FWCI
0.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Issues in Molecular Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
tau protein, neuroinflammation, Alzheimer's disease, tau phosphorylation, tau acetylation, microglia, astrocytes, anti-tau antibodies, amyloid-beta immunotherapy, neurodegenerative diseases

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