Evidence map›Paper›PMID 27557632›Full record

ArticleScientific reports2016

HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease.

Kyota Fujita, Kazumi Motoki, Kazuhiko Tagawa, Xigui Chen, Hiroshi Hama, Kazuyuki Nakajima, Hidenori Homma, Takuya Tamura, Hirohisa Watanabe, Masahisa Katsuno and 7 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
107citing papers in PubMed, 2 pooled it
5.1field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

107 citing papers in PubMed, 2 syntheses or guidelines pooled it, 151 citations in OpenAlex.

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  15. Current Evidence on the Involvement of RAGE-Diaph1 Signaling in the Pathology and Treatment of Neurodegenerative Diseases-An Overview.Pathophysiology : the official journal of the International Society for Pathophysiology · 2025
    Review
  16. Article
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  18. Unraveling sex differences in Alzheimer's disease and related endophenotypes with brain proteomes.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
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47 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors at 5 institutions in 1 country.

Kyota FujitaDepartment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Kazumi MotokiDepartment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Kazuhiko TagawaDepartment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Xigui ChenDepartment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Hiroshi HamaLaboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Kazuyuki NakajimaDepartment of Bioinformatics, Institute of Bioinformatics, Soka university, 1-236 Tangi-machi, Hachioji, Tokyo 192-8577, Japan.
Hidenori HommaDepartment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Takuya TamuraDepartment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Hirohisa WatanabeDepartment of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Masahisa KatsunoDepartment of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Chiemi MatsumiMedical and Biological Laboratories Co., LTD. 4-5-3 Sakae, Naka-ku, Nagoya 460-0008, Japan.
Masunori KajikawaMedical and Biological Laboratories Co., LTD. 4-5-3 Sakae, Naka-ku, Nagoya 460-0008, Japan.
Takashi SaitoLaboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Takaomi SaidoLaboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Gen SobueDepartment of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Atsushi MiyawakiLaboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Hitoshi OkazawaDepartment of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Tokyo Medical and Dental University · JPRIKEN Center for Brain Science · JPNagoya University · JPMedical & Biological Laboratories (Japan) · JPSoka University · JP

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsAntibodies, MonoclonalDisease Models, AnimalHMGB1 ProteinHumansMiceMitogen-Activated Protein KinasesMolecular Targeted TherapyMyristoylated Alanine-Rich C Kinase SubstrateNeuritesPhosphorylationSerinetau ProteinsToll-Like Receptor 4Amyloid beta-PeptidesAntibodies, MonoclonalHMGB1 ProteinHMGB1 protein, humanMAPT protein, humanMARCKS protein, humanMitogen-Activated Protein KinasesMyristoylated Alanine-Rich C Kinase SubstrateSerinetau ProteinsTLR4 protein, humanToll-Like Receptor 4

Identifiers

PMID27557632
PMCPMC4997258
OpenAlexW2514294261

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.