Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau

Yi-Jun Xu; Tan Wu; Larry Tso-Lun Lo; Chi-Chiu Ko; Xin Wang; Chi Him Eddie Ma

doi:10.1002/advs.202505421

Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau

Yi-Jun Xu
, Tan Wu
, Larry Tso-Lun Lo
, Chi-Chiu Ko
, Xin Wang
, Chi Him Eddie Ma^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

2 Citations (Scopus)

14 Downloads (CityUHK Scholars)

Abstract

Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H₄R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H₄R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD.
© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

Original language	English
Article number	e05421
Number of pages	22
Journal	Advanced Science
Volume	13
Issue number	2
Online published	24 Oct 2025
DOIs	https://doi.org/10.1002/advs.202505421
Publication status	Published - 9 Jan 2026

Funding

This work was supported in part by the Innovation and Technology Commission of the Hong Kong Special Administrative Region (HKSAR) Government (Grant No. ITS/099/23FP), the Research Grant Council of the HKSAR Government (Grant Nos. R1005\u201024F and CityU 11100424), the Health and Medical Research Fund, Food and Health Bureau, HKSAR Government (Grant No. 08193956) awarded to C.H.E.M., and the National Natural Science Foundation of China (Grant No. 32400807) awarded to Y.\u2010J.X.

Research Keywords

Alzheimer's disease
cAMP/TGF-β1/Smad3
histamine receptor
in silico small-molecule bioinformatics analysis
low-dose ionizing radiation
microglial phagocytosis
VUF6002

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

RGC Funding Information

RGC-funded

Access Output

10.1002/advs.202505421

362157261.pdfFinal Published version, 5.33 MBLicence: CC BY

Other Access Options

Check CityUHK Library

Permanent Link

Right click to copy link

Cite this

@article{129b693c3f5246a8b3674770fe15cd0d,

title = "Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau",

abstract = "Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD. {\textcopyright} 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.",

keywords = "Alzheimer's disease, cAMP/TGF-β1/Smad3, histamine receptor, in silico small-molecule bioinformatics analysis, low-dose ionizing radiation, microglial phagocytosis, VUF6002",

author = "Yi-Jun Xu and Tan Wu and Lo, \{Larry Tso-Lun\} and Chi-Chiu Ko and Xin Wang and Ma, \{Chi Him Eddie\}",

year = "2026",

month = jan,

day = "9",

doi = "10.1002/advs.202505421",

language = "English",

volume = "13",

journal = "Advanced Science",

issn = "2198-3844",

publisher = "Wiley-VCH Verlag GmbH",

number = "2",

}

TY - JOUR

T1 - Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau

AU - Xu, Yi-Jun

AU - Wu, Tan

AU - Lo, Larry Tso-Lun

AU - Ko, Chi-Chiu

AU - Wang, Xin

AU - Ma, Chi Him Eddie

PY - 2026/1/9

Y1 - 2026/1/9

N2 - Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD. © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

AB - Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD. © 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

KW - Alzheimer's disease

KW - cAMP/TGF-β1/Smad3

KW - histamine receptor

KW - in silico small-molecule bioinformatics analysis

KW - low-dose ionizing radiation

KW - microglial phagocytosis

KW - VUF6002

UR - https://www.scopus.com/pages/publications/105019708593

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105019708593&origin=recordpage

U2 - 10.1002/advs.202505421

DO - 10.1002/advs.202505421

M3 - RGC 21 - Publication in refereed journal

SN - 2198-3844

VL - 13

JO - Advanced Science

JF - Advanced Science

IS - 2

M1 - e05421

ER -

Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

RIF: Development and Validation of Novel Therapeutic Agents for Glaucoma Treatment through Integrated Preclinical and Clinical Studies with A Drug Repurposing Approach

ITF: Metabolomic Analysis Identifies Metabolites as Novel Therapeutic Targets for Alzheimer's Disease

GRF: Elucidating The Novel Roles of Histamine H4 Receptor in Traumatic Optic Neuropathy and As a Therapeutic Target for Glaucoma

Cite this

Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau

Abstract

Funding

Research Keywords

Publisher's Copyright Statement

RGC Funding Information

Access Output

Other Access Options

Permanent Link

Other Files and Links

Fingerprint

Projects

RIF: Development and Validation of Novel Therapeutic Agents for Glaucoma Treatment through Integrated Preclinical and Clinical Studies with A Drug Repurposing Approach

ITF: Metabolomic Analysis Identifies Metabolites as Novel Therapeutic Targets for Alzheimer's Disease

GRF: Elucidating The Novel Roles of Histamine H4 Receptor in Traumatic Optic Neuropathy and As a Therapeutic Target for Glaucoma

Cite this