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Deletion of RGS5 attenuates high-fat diet-induced cerebrovascular pathology and associated spatial memory deficits

Elabi, Osama F LU ; Tiwari, Shubhangini LU ; Garcia-Serrano, Alba M LU ; Carlsson, Robert LU orcid ; Polo, Carlos Noriega LU orcid ; Fonseca-Fonseca, Luis A LU orcid ; Duarte, João M N LU orcid and Paul, Gesine LU orcid (2026) In Brain, Behavior, and Immunity
Abstract

Diet-induced metabolic dysregulation is associated with cerebral microvascular pathology contributing to cognitive decline and vascular dementia. These alterations include blood-brain barrier (BBB) leakage, pericyte dysfunction, aberrant angiogenesis, and perivascular neuroinflammation. Restoration of BBB integrity has been achieved in other conditions by targeting pericytes, for example through knockout of Regulator of G-protein Signaling 5 (RGS5), a sensor protein for hypoxia and oxidative stress highly enriched in these cells. It remains unclear whether deletion of RGS5 can provide vascular protection in conditions of chronic metabolic stress and prevent cognitive impairment despite ongoing metabolic dysfunction. We used... (More)

Diet-induced metabolic dysregulation is associated with cerebral microvascular pathology contributing to cognitive decline and vascular dementia. These alterations include blood-brain barrier (BBB) leakage, pericyte dysfunction, aberrant angiogenesis, and perivascular neuroinflammation. Restoration of BBB integrity has been achieved in other conditions by targeting pericytes, for example through knockout of Regulator of G-protein Signaling 5 (RGS5), a sensor protein for hypoxia and oxidative stress highly enriched in these cells. It remains unclear whether deletion of RGS5 can provide vascular protection in conditions of chronic metabolic stress and prevent cognitive impairment despite ongoing metabolic dysfunction. We used constitutional RGS5 knockout (KO) mice and wildtype (WT) controls fed a standard or high-fat diet (HFD) for 23 weeks to induce metabolic dysfunction, confirmed by weight gain, insulinemia, and impaired glucose tolerance. BBB leakage, vascular pathology (vessel density, branching, pericyte density and coverage), microglial activation and microglia-capillary interactions were analyzed using immunohistochemistry. Spatial memory was evaluated using the novel object location test. HFD induced obesity, glucose intolerance and insulin resistance in all mice. In WT but not RGS5-KO mice, HFD caused BBB leakage, immature angiogenesis, and pericyte activation. RGS5 deletion also prevented microglial activation and enhanced interactions between resting microglia and striatal vessels. Importantly, HFD-induced impairment of spatial memory was prevented in KO mice. These data suggest that deletion of RGS5 preserves BBB integrity, maintains microvascular homeostasis, reduces neuroinflammation, and ameliorates memory decline in diet-induced metabolic dysfunction. These findings highlight RGS5 as potential therapeutic target and emphasize microvascular dysfunction as contributor to HFD-induced cognitive decline.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Brain, Behavior, and Immunity
article number
106950
publisher
Elsevier
external identifiers
  • pmid:42575451
  • scopus:105046927084
ISSN
1090-2139
DOI
10.1016/j.bbi.2026.106950
language
English
LU publication?
yes
additional info
Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.
id
981281a6-4adc-4c32-8845-6fb73415cd77
date added to LUP
2026-08-11 08:39:02
date last changed
2026-09-13 04:01:36
@article{981281a6-4adc-4c32-8845-6fb73415cd77,
  abstract     = {{<p>Diet-induced metabolic dysregulation is associated with cerebral microvascular pathology contributing to cognitive decline and vascular dementia. These alterations include blood-brain barrier (BBB) leakage, pericyte dysfunction, aberrant angiogenesis, and perivascular neuroinflammation. Restoration of BBB integrity has been achieved in other conditions by targeting pericytes, for example through knockout of Regulator of G-protein Signaling 5 (RGS5), a sensor protein for hypoxia and oxidative stress highly enriched in these cells. It remains unclear whether deletion of RGS5 can provide vascular protection in conditions of chronic metabolic stress and prevent cognitive impairment despite ongoing metabolic dysfunction. We used constitutional RGS5 knockout (KO) mice and wildtype (WT) controls fed a standard or high-fat diet (HFD) for 23 weeks to induce metabolic dysfunction, confirmed by weight gain, insulinemia, and impaired glucose tolerance. BBB leakage, vascular pathology (vessel density, branching, pericyte density and coverage), microglial activation and microglia-capillary interactions were analyzed using immunohistochemistry. Spatial memory was evaluated using the novel object location test. HFD induced obesity, glucose intolerance and insulin resistance in all mice. In WT but not RGS5-KO mice, HFD caused BBB leakage, immature angiogenesis, and pericyte activation. RGS5 deletion also prevented microglial activation and enhanced interactions between resting microglia and striatal vessels. Importantly, HFD-induced impairment of spatial memory was prevented in KO mice. These data suggest that deletion of RGS5 preserves BBB integrity, maintains microvascular homeostasis, reduces neuroinflammation, and ameliorates memory decline in diet-induced metabolic dysfunction. These findings highlight RGS5 as potential therapeutic target and emphasize microvascular dysfunction as contributor to HFD-induced cognitive decline.</p>}},
  author       = {{Elabi, Osama F and Tiwari, Shubhangini and Garcia-Serrano, Alba M and Carlsson, Robert and Polo, Carlos Noriega and Fonseca-Fonseca, Luis A and Duarte, João M N and Paul, Gesine}},
  issn         = {{1090-2139}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Elsevier}},
  series       = {{Brain, Behavior, and Immunity}},
  title        = {{Deletion of RGS5 attenuates high-fat diet-induced cerebrovascular pathology and associated spatial memory deficits}},
  url          = {{http://dx.doi.org/10.1016/j.bbi.2026.106950}},
  doi          = {{10.1016/j.bbi.2026.106950}},
  year         = {{2026}},
}