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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

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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.

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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.

Funding

This study was supported by funding from the Agencia Nacional de Promoción Científica y Tecnológica (PICT-2015-0285, PICT-2016-4647, and PIBT/09 2013 to LM; PICT-2015-2812 to FJP; PICT-2013-318 to EMC), Consejo Nacional de Investigaciones Científicas y Técnicas (PIP-0378 to LM), Canadian Institutes of Health Research (201603PJT-364544 to ACC). PVMA and JCC are supported by CONICET fellowships. MIF is member of the Technical Career of CONICET. PG, MCL, CCF, MCD, MP, CS, MA, EMC, FJP, and LM are members of the Research Career of CONICET. SDC is the holder of the Charles E. Frosst/Merck Research Associate position. ACC is member of the Canadian Consortium of Neurodegeneration in Aging (CCNA) and holder of the McGill University Charles E. Frosst/Merck Chair in Pharmacology.

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  1. Pablo Galeano and María C. Leal contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Amyloidosis and Neurodegeneration, Fundación Instituto Leloir, IIBBA-CONICET, Av. Patricias Argentinas 435, C1405BWE, Ciudad Autónoma de Buenos Aires, Argentina

    Pablo Galeano, María C. Dalmasso, Pamela V. Martino Adami, Eduardo M. Castaño & Laura Morelli

  2. Laboratory of Protective and Regenerative Therapies of the CNS, Fundación Instituto Leloir, IIBBA-CONICET, Av. Patricias Argentinas 435, C1405BWE, CABA, Argentina

    María C. Leal, María I. Farías, Juan C. Casabona, Mariana Puntel & Fernando J. Pitossi

  3. Institute of Basic Science and Experimental Medicine (ICBME), Instituto Universitario del Hospital Italiano de Buenos Aires (HIBA), Potosí 4240, C1199ACL, CABA, Argentina

    Carina C. Ferrari

  4. Department of Pharmacology and Therapeutics, McGill University, McIntyre Medical Building 3655 Prom. Sir-William-Osler, Montreal, QC, H3G 1Y6, Canada

    Sonia Do Carmo & A. Claudio Cuello

  5. Laboratory of Nuclear Magnetic Resonance, Fundación Instituto Leloir, IIBBA-CONICET, Av. Patricias Argentinas 435, C1405BWE, CABA, Argentina

    Clara Smal & Martín Arán

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  1. Pablo Galeano
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Galeano, P., Leal, M.C., Ferrari, C.C. et al. 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. Mol Neurobiol 55, 8637–8650 (2018). https://doi.org/10.1007/s12035-018-1002-3

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