Deletion of Small GTPase H-Ras Rescues Memory Deficits and Reduces Amyloid Plaque-Associated Dendritic Spine Loss in Transgenic Alzheimer’s Mice

Wenhui Qu, Angela Jeong, Rui Zhong, Josslen S. Thieschafer, Andrea L Gram, Ling Li

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder, affecting millions of lives without a cure. While the molecular mechanism of AD remains obscure, emerging evidence suggests that small GTPases, a group of GTP-binding proteins that regulate a plethora of essential cellular events, modulate the pathogenic process of AD. Among those, the small GTPase H-Ras, extensively studied in cancer, regulates synaptic function, and both upstream and downstream signaling pathways of H-Ras have been implicated in AD. However, the role of H-Ras per se in AD pathogenesis had not been explored previously. In the present study, the impact of Hras deletion on cognitive function and amyloid pathology was investigated in transgenic APP/PS1 mice of AD. Behavioral assessments showed that the absence of Hras rescued spatial memory deficit in APP/PS1 mice at 9 months of age. The pathological evaluation demonstrated that Hras deletion reduced cortical amyloid deposition and astrogliosis. Furthermore, Hras deficiency protected against amyloid plaque-associated loss of dendritic spines in APP/PS1 mice. Intriguingly, canonical signaling pathways downstream of H-Ras were not affected by the absence of Hras in the brain. Unbiased transcriptomic analysis revealed that lack of H-Ras affected the expression of select genes in the brain of AD mice and identified a novel connection between H-Ras and Annexin A4, a calcium-dependent phospholipid-binding protein that has been shown to regulate membrane repair, neuroinflammation, and calcium homeostasis. Taken together, these data indicate that H-Ras modifies the pathogenic process of AD and may serve as a potential therapeutic target for AD.

Original languageEnglish (US)
Pages (from-to)495-511
Number of pages17
JournalMolecular neurobiology
Volume60
Issue number2
DOIs
StatePublished - Feb 2023

Bibliographical note

Funding Information:
We thank the University of Minnesota Informatics Institute and Juan E. Abrahante Lloréns for the initial RNA-seq data analysis.

Funding Information:
This work was supported in part by grants from the National Institute on Aging of the National Institutes of Health (RF1AG056976 and RF1AG058081), and the College of Pharmacy and the Office of Clinical Affairs Faculty Research Development Program at the University of Minnesota.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • Alzheimer’s disease
  • Cognitive function
  • H-Ras
  • Neuropathology
  • Small GTPase
  • Transgenic mice

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Deletion of Small GTPase H-Ras Rescues Memory Deficits and Reduces Amyloid Plaque-Associated Dendritic Spine Loss in Transgenic Alzheimer’s Mice'. Together they form a unique fingerprint.

Cite this