Adult hippocampal Notch activation impairs ABeta clearance and cognition in a rat model of Alzheimer

GALEANO, PABLO; LEAL, MARÍA CELESTE; FERRARI, CARINA CINTIA; DALMASSO, MARÍA CAROLINA; MARTINO-ADAMI, PAMELA VICTORIA; FARÍAS, MARÍA ISABEL; PITOSSI, FERNANDO JUAN; MORELLI, LAURA

Córdoba

Congreso; 52 Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2016

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular (SAIB)

Background: Along the entire lifetime, Notch is actively involved in dynamic changes in the cellular architecture and function of the nervous system. It controls neurogenesis, growth of axons and dendrites, synaptic plasticity and neuronal death. The specific roles of Notch in adult brain plasticity and neurological disorders have begun to be unraveled in recent years, and experimental evidence suggest that Notch is operative in diverse brain pathologies including Alzheimer´s disease (AD), however the mechanisms remain unknown. Objective: To study whether chronic Notch-1 activation exacerbates ABeta associated pathology in a rat model of early AD. Methods: Two month-old transgenic McGill-R-Thy1-APP rats (Tg+/-) were injected with lentiviral particles (LVP) expressing the transcriptionally active proteolytic fragment of Notch-1 (NICD) (n=9) or a fluorescent protein Tomato (TOM) (n=10). At 6 months, spatial cognition was assessed and hippocampal ABeta levels were quantified using a multiplex electrochemiluminescence ELISA test. Results: Tg-NICD rats displayed short-term spatial memory impairment, increments on hippocampal ABeta40/ABeta42 levels and decrements of neurotoxic ABeta species in cerebrospinal fluid (CSF) as compared to Tg-TOM. Conclusions: chronic expression of NICD in adult brain impacts on ABeta metabolism and worsen cognition suggesting a pathway linking Notch-1 signaling and AD pathology.