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

GALEANO P; LEAL MC; FERRARI CC; DALMASSO MC; MARTINO ADAMI PV; FARÍAS MI; CASTAÑO EM; PITOSSI F ; MORELLI L

Cordoba

Congreso; SAIB - 5 2 th Annual Meeting Argentine Society for Biochemistry and Molecular Biology L I I Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología Molecular; 2016

SAIB

Background: Along the entire lifetime, Notch isactively involved in dynamic changes in the cellular architecture and functionof the nervous system. It controls neurogenesis, the growth of axons anddendrites, synaptic plasticity, and neuronal death. The specific roles of Notchin adult brain plasticity and neurological disorders have begun to be unraveledin recent years, and experimental evidence suggest that Notch is operative indiverse brain pathologies including Alzheimer´s disease (AD) however themechanisms remain unknown. Objective: Tostudy whether chronic Notch1 activation exacerbates Aβ associated pathology ina rat model of early AD. Methods: Twomonth-old transgenic McGill-R-Thy1-APP rats (Tg+/-) were injected with lentiviralparticles (LVP) expressing the transcriptionally active proteolytic fragment ofNotch1 (NICD) (n=9) or a fluorescent protein Tomato (TOM) (n=10). At 6 months,spatial cognition was assessed and hippocampal Aβ levels were quantified using amultiplex electrochemiluminescence ELISA test. Results: Tg-NICD rats displayed short-term spatial memoryimpairment, increments on hippocampal Aβ40/Aβ42 levels and decrements ofneurotoxic Aβ species in cerebrospinal fluid (CSF) as compared to Tg-TOM. Conclusions: chronic expression of NICDin adult brain impacts on Aβ metabolism and worsen cognition suggesting apathway linking Notch1 signaling and AD pathology