Chronic Hippocampal Expression of Notch Intracellular Domain Induces Vascular Thickening, Reduces Glucose Availability, and Exacerbates Spatial Memory Deficits in a Rat Model of Early Alzheimer

  • Pablo Galeano
  • María C. Leal
  • Carina C. Ferrari
  • María C. Dalmasso
  • Pamela V. Martino Adami
  • María I. Farías
  • Juan C. Casabona
  • Mariana Puntel
  • Sonia Do Carmo
  • Clara Smal
  • Martín Arán
  • Eduardo M. Castaño
  • Fernando J. Pitossi
  • A. Claudio Cuello
  • Laura Morelli
Article

Abstract

The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. A number of independent studies have shown significant increases of Notch expression in brains from patients at later stages of sporadic Alzheimer’s disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD is still elusive. To further investigate this issue, 2-month-old wild-type (WT) and hemizygous McGill-R-Thy1-APP rats (Tg(+/−)) were injected in CA1 with lentiviral particles (LVP) expressing the transcriptionally active fragment of Notch, known as Notch Intracellular Domain (NICD), (LVP-NICD), or control lentivirus particles (LVP-C). The Tg(+/−) rat model captures presymptomatic aspects of the AD pathology, including intraneuronal amyloid beta (Aβ) accumulation and early cognitive deficits. Seven months after LVP administration, Morris water maze test was performed, and brains isolated for biochemical and histological analysis. Our results showed a learning impairment and a worsening of spatial memory in LVP-NICD- as compared to LVP-C-injected Tg(+/−) rats. In addition, immuno histochemistry, ELISA multiplex, Western blot, RT-qPCR, and 1H-NMR spectrometry of cerebrospinal fluid (CSF) indicated that chronic expression of NICD promoted hippocampal vessel thickening with accumulation of Aβ in brain microvasculature, alteration of blood-brain barrier (BBB) permeability, and a decrease of CSF glucose levels. These findings suggest that, in the presence of early Aβ pathology, expression of NICD may contribute to the development of microvascular abnormalities, altering glucose transport at the BBB with impact on early decline of spatial learning and memory.

Keywords

Spatial memory decline Learning impairment Notch intracellular domain (NICD) Early Alzheimer’s disease Neuroinflammation Blood-brain barrier permeability 

Notes

Acknowledgments

We acknowledge the helpful comments of Dr. Arthur S. Edison (Departments of Genetics and Biochemistry, Institute of Bioinformatics and Complex Carbohydrate Center, University of Georgia) on the NMR experiments.

Supplementary material

12035_2018_1002_MOESM1_ESM.pdf (616 kb)
ESM 1 (PDF 616 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Pablo Galeano
    • 1
  • María C. Leal
    • 2
  • Carina C. Ferrari
    • 3
  • María C. Dalmasso
    • 1
  • Pamela V. Martino Adami
    • 1
  • María I. Farías
    • 2
  • Juan C. Casabona
    • 2
  • Mariana Puntel
    • 2
  • Sonia Do Carmo
    • 4
  • Clara Smal
    • 5
  • Martín Arán
    • 5
  • Eduardo M. Castaño
    • 1
  • Fernando J. Pitossi
    • 2
  • A. Claudio Cuello
    • 4
  • Laura Morelli
    • 1
  1. 1.Laboratory of Amyloidosis and NeurodegenerationFundación Instituto Leloir, IIBBA-CONICETCiudad Autónoma de Buenos AiresArgentina
  2. 2.Laboratory of Protective and Regenerative Therapies of the CNSFundación Instituto Leloir, IIBBA-CONICETCABAArgentina
  3. 3.Institute of Basic Science and Experimental Medicine (ICBME)Instituto Universitario del Hospital Italiano de Buenos Aires (HIBA)CABAArgentina
  4. 4.Department of Pharmacology and TherapeuticsMcGill UniversityMontrealCanada
  5. 5.Laboratory of Nuclear Magnetic ResonanceFundación Instituto Leloir, IIBBA-CONICETCABAArgentina

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