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Review
. 2020 Feb 7;9(2):383.
doi: 10.3390/cells9020383.

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

Yam Nath Paudel  1 , Efthalia Angelopoulou  2 , Christina Piperi  2 , Iekhsan Othman  1 , Khurram Aamir  3 , Mohd Farooq Shaikh  1
Affiliations
Review

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

Yam Nath Paudel et al. Cells. .

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.

Keywords: Alzheimer’s disease; HMGB1; Neuroinflammation; RAGE; TLR4.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
HMGB1/RAGE and HMGB1/TLR4 signaling pathways in AD: HMGB1 can interact with extracellular Aβ peptides and decrease Aβ deposition by inhibiting Aβ clearance by microglia, as well as increasing β- and γ-secretase activity. RAGE enhances production of Aβ, abnormal Tau hyperphosphorylation, and NFTs formation. HMGB1/RAGE and HMGB1/TLR4 signaling induce neuroinflammation by activating the NF-κB pathway, increasing production of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β, activating microglia and astrocytes in a reactive and inflammatory state, and thus aggravating the AD pathogenesis through a vicious cycle of inflammation and oxidative damage. RAGE/CaMKK-β-AMPK, the RAGE/ERK1/2, RAGE/GSK-3β, and RAGE/NF-κB pathways have been involved in the regulation of abnormal Tau hyperphosphorylation and Aβ pathology. RAGE signaling has been also implicated in synaptic dysfunction, reduced AChE activity, and neurodegeneration. However, activation of RAGE/NF-κB pathway by HMGB1 in adult NPCs promotes neuronal differentiation and formation of new neurons, leading to increased adult neurogenesis. In addition, HMGB1 may play dual roles in AD pathogenesis, since it can also contribute to reparative mechanisms in the AD brain. AD, Alzheimer’s disease; HMGB1, High mobility group box 1; RAGE, Receptor for advanced glycation end products; TLR4, Toll-like receptor 4; Aβ, Amyloid beta; NFTs, Neurofibrillary tangles; CaMKK-β,Ca2+/calmodulin-dependent protein kinase kinase-β; ERK1/2, Extracellular signal regulated kinase ½; NPCs, Neural progenitor cells; IL, Interleukin; NF-κβ, Nuclear factor κ light chain enhancer of activated β cells; TNF-α, Tumor necrosis factor-α.
Figure 2
Figure 2
Beneficial effect of HMGB1, RAGE, and TLR4 inhibition in AD.
See this image and copyright information in PMC

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