Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.
Highlights
Alzheimer’s disease (AD) is a progressive complex neurodegenerative disorder and an emerging global health concern, afflicting around 50 million worldwide [1]
Accumulative evidence highlights the pathogenic role of high mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE), and toll-like receptor 4 (TLR4) signaling in AD onset
HMGB1 has been demonstrated to mediate neuroinflammation, and participate in the process of neurodegeneration [32,33]. These data suggest that development of novel pharmacological modulators that can modulate HMGB1 and its receptors (RAGE and TLR4) and control or reduce neuroinflammation may present additional therapeutic strategies to current AD treatment
Summary
Alzheimer’s disease (AD) is a progressive complex neurodegenerative disorder and an emerging global health concern, afflicting around 50 million worldwide [1]. AD occurs in two major forms, known as sporadic AD and familial AD The former is most common (90% of AD cases), affecting people of any age, but mainly above the age of 65 years and it is often referred as late-onset AD (LOAD) [3]. RAGE plays a significant role in neurodegeneration, whereas TLR4, being an immune cell receptor, regulates immune response [18]. Both receptors share common signaling pathways to induce inflammation [11] and they have been implicated in the pathogenesis of several diseases with therapeutic targeting potential [12]. Accumulative evidence highlights the pathogenic role of HMGB1, RAGE, and TLR4 signaling in AD onset. We discuss the pathogenic role of HMGB1 and its principal receptors in AD pathology along with their biomarker potential and the promising clinical outcome of blocking/inhibiting HMGB1, RAGE, and TLR4 in AD experimental studies
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