HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease
Open accessAbstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis is predominantly attributed to the aggregation and transmission of two molecules, Aβ and tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network, occurs at Ser46 prior to aggregation of Aβ and is sustained throughout the course of AD in human and mouse brains. Furthermore, HMGB1 released from necrotic or hyperexcitatory neurons binds to TLR4, triggers the specific phosphorylation of MARCKS via MAP kinases and induces neurite degeneration, the classical hallmark of AD pathology. Subcutaneous injection of a newly developed monoclonal antibody against HMGB1 strongly inhibits neurite degeneration even in the presence of Aβ plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and Aβ mutually affect polymerization of the other molecule and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by Aβ-dependent and Aβ-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with Aβ and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The phosphorylation level of MARCKS is associated with Aβ biogenesis and neuron degeneration.
“MARCKS is the main substrate for PKC, and the phosphorylation level of MARCKS is associated with Aβ biogenesis and neuron degeneration. 53 , 54 , 73”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [54]
The Results sections on MARCKS phosphorylation report that phosphorylated MARCKS is found near Aβ aggregates and that phosphorylation-mimicking mutants reduce neurite length and spine density in mouse neurons (page numbers unavailable). The paper supports an association with neurite degeneration, but it does not establish an association between MARCKS phosphorylation and Aβ biogenesis; its Aβ findings concern accumulation and aggregation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMARCKS is the main substrate for PKC.
“MARCKS is the main substrate for PKC, and the phosphorylation level of MARCKS is associated with Aβ biogenesis and neuron degeneration. 53 , 54 , 73”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [54]
The paper’s Abstract (page unavailable) calls MARCKS a “representative substrate” of PKC, and the Results identify PKC as a MARCKS kinase. These passages support the substrate relationship but do not establish that MARCKS is PKC’s main substrate. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe phosphorylation level of MARCKS is associated with AD.
“MARCKS is a cellular substrate for protein kinase C (PKC) (Figure S5) and the phosphorylation level of MARCKS is associated with AD. 53 , 54”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [54]
MARCKS is a cellular substrate for protein kinase C (PKC).
“MARCKS is a cellular substrate for protein kinase C (PKC) (Figure S5) and the phosphorylation level of MARCKS is associated with AD. 53 , 54”
From Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes (2025) · cites this paper as [54]
17% of the 93 differentially phosphorylated proteins are known to be central molecular players in focal adhesion signaling.
“17% are known to be central molecular players in focal adhesion sig naling (Fig. 6 D and Fig. S5, A and B; Farhadi and Park, 2025; Fujita et al., 2016; Geiger, 2006; Henderson et al., 2019; Huveneers and Danen, 2009; Islam et al., 2025; Ma”
From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Fujita et al., 2016
The Abstract reports 17 proteins with abnormal phosphorylation in Alzheimer’s disease models, but does not identify a set of 93 proteins or classify any percentage as central to focal adhesion signaling. The Results section on MARCKS phosphorylation and the targeted searches for focal adhesion, 93 proteins, and 17% likewise provide no passage addressing that classification. Page numbers are unavailable in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Treatment with anti-HMGB1 antibodies or HMGB1 release inhibitors decreases Alzheimer's disease-associated neuropathology, reduces the burden of senescent cells in the brain, alleviates neuroinflammation, and improves cognitive function in Alzheimer's disease mouse models.
“treatment with anti‐HMGB1 antibodies or HMGB1 release inhibitors decreases AD‐associated neuropathology, reduces the burden of senescent cells in the brain, alleviates neuroinflammation, and improves cognitive function in AD mouse models. 89”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [89]
Elevated HMGB1 levels are found in the brain and cerebrospinal fluid of Alzheimer's disease patients and aged rodents and correlate with disease severity.
“elevated HMGB1 levels are found in the brain and CSF of AD patients and aged rodents and correlate with disease severity. 88 , 89 , 90”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [89]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 65 · Cited by 160
- Authors
- Fujita, K., Motoki, K., Tagawa, K., Chen, X., Hama, H., Nakajima, K., Homma, H., Tamura, T., Watanabe, H., Katsuno, M., Matsumi, C., Kajikawa, M., Saito, T., Saido, T., Sobue, G., Miyawaki, A., & Okazawa, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- RIKEN Center for Brain Science (JP)
- Soka University (JP)
- Nagoya University (JP)
- Medical & Biological Laboratories (Japan) (JP)
- Corresponding author
- Okazawa, Hitoshi
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-08-25
- Volume
- 6
- Issue
- 1
- Pages
- 31895-31895
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4997258
- OpenAlex
- W2514294261
- Cited by
- 160
- References
- 65
- Citations by year
- 2026: 20 · 2025: 12 · 2024: 18 · 2023: 17 · 2022: 14 · 2021: 31 · 2020: 21 · 2019: 11 · 2018: 9 · 2017: 5 · 2016: 1
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- Foundation of Synapse and Neurocircuit Pathology
- Japan Society for the Promotion of Science (16H02655, 16K07040, 26290019)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- HMGB1, Alzheimer's disease, TLR4, MARCKS, neurite degeneration, amyloid-beta, tau protein, MAPK signaling, monoclonal antibody therapy, actin cytoskeleton, cognitive impairment, therapeutic target
- MeSH terms
- Myristoylated Alanine-Rich C Kinase Substrate, Alzheimer Disease, Animals, Antibodies, Monoclonal, Disease Models, Animal, Humans, Phosphorylation, Serine, Amyloid beta-Peptides, Neurites, tau Proteins, Mitogen-Activated Protein Kinases, HMGB1 Protein, Toll-Like Receptor 4, Mice, Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
