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

GALEANO, PABLO; LEAL, MARÍA C.; FERRARI, CARINA C.; DALMASSO, MARÍA C.; MARTINO ADAMI, PAMELA V.; FARÍAS, MARÍA I.; CASABONA, JUAN C.; PUNTEL, MARIANA; DO CARMO, SONIA; SMAL, CLARA; ARÁN, MARTÍN; CASTAÑO, EDUARDO M.; PITOSSI, FERNANDO J.; CUELLO, A. CLAUDIO; MORELLI, LAURA

MOLECULAR NEUROBIOLOGY

HUMANA PRESS INC

Lugar: Oregon; Año: 2018

0893-7648

The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. Anumber of independent studies have shown significant increases of Notch expression in brains from patients at later stages ofsporadic Alzheimer?s disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD isstill 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 NotchIntracellular 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. Sevenmonths after LVP administration, Morris water maze test was performed, and brains isolated for biochemical and histologicalanalysis. Our results showed a learning impairment and a worsening of spatial memory in LVP-NICD- as compared to LVP-Cinjected Tg(+/−) rats. In addition, immuno histochemistry, ELISA multiplex, Western blot, RT-qPCR, and 1 H-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 Aβpathology, 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.