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

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.

High expression of the HMGB1–TLR4 axis and its downstream signaling factors in patients with Parkinson's disease and the relationship of pathological staging

“…An HMGB1‐based neuroinflammation study found HMGB1 to have a neurotrophic factor‐like effect (Li et al., 2016). Intracerebroventricular injection of HMGB1 was found to promote TNF‐α and IL‐6 expressions in mouse brain tissues (Fujita et al., 2016). The injection of HMGB1 into the mouse parietal lobe resulted in the partial elevation of iNOS and IL‐1β mRNA expressions 24 hr later.…”

Impact of HMGB1, RAGE, and TLR4 in Alzheimer’s Disease (AD): From Risk Factors to Therapeutic Targeting

“…In an animal model of early AD monitoring, using 5xFAD transgenic mice, HMGB1 was shown to initiate neurite degeneration with TLR4-myristoylated alanine-rich C-kinase substrate (MARCKS), triggering MARCKS phosphorylation [37]. In fact, HMGB1 initiated neurite degeneration independent of Aβ and the process of Aβ aggregation by disrupting the balance between different Aβ isoforms [37]. HMGB1 was released from necrotic neurons with intracellular Aβ, thus proposing that HMGB1 occurs downstream of the established intracellular Aβ toxicity.…”

“…HMGB1 was released from necrotic neurons with intracellular Aβ, thus proposing that HMGB1 occurs downstream of the established intracellular Aβ toxicity. The association between HMGB1 and Aβ is therefore bi-directional and HMGB1 may be considered as an independent AD mediator, closely related to the amyloid cascade [37].…”

Pathway-Phenotypes of Non-responders and Partial Responders to Treatment With Antipsychotics in Schizophrenia: A Machine Learning Study

“…These results show that non-remission in schizophrenia is partly determined by activated neuroimmune pathways and residual neurocognitive deficits, which additionally may be induced by HMGB1 (13). HMGB1 is released from necrotic cells thereby stimulating the production of proinflammatory cytokines, including IL-6, and neurotoxic factors leading to BBB breakdown and neurodegenerative processes, which are associated with memory impairments (62)(63)(64)(65). Most importantly, we observed that using SIMCA, all controls were authenticated as belonging to the control class, and all PRTT were authenticated a belonging to the PRTT class.…”