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Background <p>Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are increasingly recognized as key contributors to the preclinical phase of Alzheimer’s disease (AD), highlighting their importance in early pathogenesis. Sensitive biomarkers that precede irreversible neuronal loss and cognitive decline are urgently needed to enable early diagnosis and intervention. This study aimed to characterize early neurovascular and metabolic alterations, along with their associated cell-type-specific transcriptional signatures, in three-month-old presymptomatic 5XFAD mice.</p> Methods <p>Water extraction with phase contrast arterial spin tagging (WEPCAST) MRI, a non-invasive, contrast-free, and clinically applicable technique, was used to assess BBB integrity in 5XFAD mice. BBB permeability to water molecules, water extraction fraction, and cerebral blood flow (CBF) were measured and used to calculate the permeability surface area product (PS). Cerebral metabolic rate of oxygen (CMRO₂) was evaluated by T2-relaxation under spin tagging (TRUST), while creatine chemical exchange saturation transfer (crCEST) MRI, a pH-sensitive measure, was employed to evaluate tissue acidification, respectively. To invesigate underlying molecular mechanisms, single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment was performed on hippocampal tissue.</p> Results <p>Three-month-old 5XFAD mice exhibit increased BBB permeability to water molecules as detected by WEPCAST MRI, despite preserved macromolecular barrier integrity assessed by Sulfo-NHS-Biotin tracer, indicating subtle BBB functional alterations and highlighting the sensitivity of WEPCAST for detecting early BBB dysfunction. At this stage, 5XFAD mice showed significantly reduced CMRO₂, reflecting impaired oxygen metabolism. In addition, a hippocampal-specific reduction in the pH-dependent exchange rate of creatine guanidinium protons was observed in AD mice, accompanied by elevated neuronal H4K12 lactylation, consistent with tissue acidification. snRNA-seq analysis revealed cell type-specific transcriptional changes, including downregulation of genes related to brain barrier function and angiogenesis in cerebral endothelia cells, dysregulation of innate immune response genes in astrocytes, and upregulation of cholesterol biosynthesis and metabolism pathway genes in CA1 excitatory neurons.</p> Conclusions <p>Our study demonstrates that BBB dysfunction and cerebral metabolic abnormalities emerge prior to brain hypoperfusion and cognitive decline in AD, underscoring their involvement in early disease mechanisms. These results identify molecular pathways and MRI-detectable biomarkers with potential utility for early diagnosis and therapeutic targeting in preclinical AD.</p>

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Neurovascular and metabolic dysfunction with cell type-specific transcriptomic changes in presymptomatic 5XFAD mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Minmin Yao,
  • Na Sun,
  • Raleigh Linville,
  • Zhiliang Wei,
  • Aaron Kakazu,
  • Yuxiao Ouyang,
  • Ruoxuan Li,
  • Lida Du,
  • Haitong Wang,
  • Yuan Zhou,
  • Yanli Jiang,
  • Ziqin Zhang,
  • Anna Li,
  • Francisco J. Garcia,
  • Hanzhang Lu,
  • Jiadi Xu,
  • Manolis Kellis,
  • Myriam Heiman,
  • Wenzhen Duan

摘要

Background

Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are increasingly recognized as key contributors to the preclinical phase of Alzheimer’s disease (AD), highlighting their importance in early pathogenesis. Sensitive biomarkers that precede irreversible neuronal loss and cognitive decline are urgently needed to enable early diagnosis and intervention. This study aimed to characterize early neurovascular and metabolic alterations, along with their associated cell-type-specific transcriptional signatures, in three-month-old presymptomatic 5XFAD mice.

Methods

Water extraction with phase contrast arterial spin tagging (WEPCAST) MRI, a non-invasive, contrast-free, and clinically applicable technique, was used to assess BBB integrity in 5XFAD mice. BBB permeability to water molecules, water extraction fraction, and cerebral blood flow (CBF) were measured and used to calculate the permeability surface area product (PS). Cerebral metabolic rate of oxygen (CMRO₂) was evaluated by T2-relaxation under spin tagging (TRUST), while creatine chemical exchange saturation transfer (crCEST) MRI, a pH-sensitive measure, was employed to evaluate tissue acidification, respectively. To invesigate underlying molecular mechanisms, single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment was performed on hippocampal tissue.

Results

Three-month-old 5XFAD mice exhibit increased BBB permeability to water molecules as detected by WEPCAST MRI, despite preserved macromolecular barrier integrity assessed by Sulfo-NHS-Biotin tracer, indicating subtle BBB functional alterations and highlighting the sensitivity of WEPCAST for detecting early BBB dysfunction. At this stage, 5XFAD mice showed significantly reduced CMRO₂, reflecting impaired oxygen metabolism. In addition, a hippocampal-specific reduction in the pH-dependent exchange rate of creatine guanidinium protons was observed in AD mice, accompanied by elevated neuronal H4K12 lactylation, consistent with tissue acidification. snRNA-seq analysis revealed cell type-specific transcriptional changes, including downregulation of genes related to brain barrier function and angiogenesis in cerebral endothelia cells, dysregulation of innate immune response genes in astrocytes, and upregulation of cholesterol biosynthesis and metabolism pathway genes in CA1 excitatory neurons.

Conclusions

Our study demonstrates that BBB dysfunction and cerebral metabolic abnormalities emerge prior to brain hypoperfusion and cognitive decline in AD, underscoring their involvement in early disease mechanisms. These results identify molecular pathways and MRI-detectable biomarkers with potential utility for early diagnosis and therapeutic targeting in preclinical AD.