Microglial Amyloid-β1-40 Phagocytosis Dysfunction Is Caused by High-Mobility Group Box Protein-1: Implications for the Pathological Progression of Alzheimer’s Disease

Abstract

In Alzheimer disease (AD) patient brains, the accumulation of amyloid-β (Aβ) peptides is associated with activated microglia. Aβ is derived from the amyloid precursor protein; two major forms of Aβ, that is, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), exist. We previously reported that rat microglia phagocytose Aβ42, and high mobility group box protein 1 (HMGB1), a chromosomal protein, inhibits phagocytosis. In the present study, we investigated the effects of exogenous HMGB1 on rat microglial Aβ40 phagocytosis. In the presence of exogenous HMGB1, Aβ40 markedly increased in microglial cytoplasm, and the reduction of extracellular Aβ40 was inhibited. During this period, HMGB1 was colocalized with Aβ40 in the cytoplasm. Furthermore, exogenous HMGB1 inhibited the degradation of Aβ40 induced by the rat microglial cytosolic fraction. Thus, extracellular HMGB1 may internalize with Aβ40 in the microglial cytoplasm and inhibit Aβ40 degradation by microglia. This may subsequently delay Aβ40 clearance. We further confirmed that in AD brains, the parts of senile plaques surrounded by activated microglia are composed of Aβ40, and extracellular HMGB1 is deposited on these plaques. Taken together, microglial Aβ phagocytosis dysfunction may be caused by HMGB1 that accumulates extracellularly on Aβ plaques, and it may be critically involved in the pathological progression of AD.

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

“…An interaction between Aβ and HMGB1 has been reported5253, but critical points remain uncertain or controversial, such as the effect of HMGB1 on the Aβ polymerization process, the effect on the Aβ monomer/oligomer/polymer ratio, and the effect of Aβ on HMGB1. Therefore, we examined these issues (Supplementary Figures 15 and 16).…”

Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound

“…Additionally, proteins associated with Aβ may contribute to the impairment of glial cells to internalize Aβ (Familian et al, 2007; Takata et al, 2012), rendering clearance of Aβ more difficult. In the current study, analysis of glial cells in regions of close proximity and distal to plaques demonstrated that distal glial cells have greater potential to increase in size and to take up Aβ after treatment.…”

HMGB1 in health and disease

“…The secreted HMGB1 impairs memory by RAGE and TLR4 (Mazarati et al, 2011). In addition, the secreted HMGB1 can aggregate to neurotic plaques and then bind Aβ, which in turn inhibits the phagocytosis and degradation of Aβ by microglial cells (Takata et al, 2003; Takata et al, 2012). …”