194 | Single chain antibody against Abeta- oligomers improves performance for some memory tasks in elderly rats

Disorders of the Nervous System

Author: Maria Victoria Oberholzer | Email: vic.ober@gmail.com

Maria Victoria Oberholzer , Alejandro Josiowicz , Natalia Claudia Colettis , Mauro Exequiel Alfaro , Mercedes Olivera , Luis Ignacio Brusco , Claudio Cuello , Ricardo Allegri 3°5°, Diana Alicia Jerusalinsky

1° IBCN – UBA – CONICET, Buenos Aires, Argentina
2° ANLIS Malbran – Buenos Aires, Argentina
3° FMed – UBA, Buenos Aires, Argentina
4° McGill University – Montreal, Canada
5° FLENI, Buenos Aires, Argentina

In early stages of Alzheimer’s disease (AD) beta-amyloid oligomers (A?O) cause synaptic impairment and memory decline as shown in animal models. NUsc1, a single chain variable-fragment antibody (scFv) that binds a subpopulation of soluble A?Os prevented A?O-induced short-term memory (STM) deficit in mice. We developed an Adeno-Associated virus-derived vector to express NUsc1 (V) in neurons. The transgenic McGill-R-Thy1-APP rat (Tg) model of AD suffers a progressive amyloid pathology, with cognitive deterioration affecting long-term memory (LTM) of object recognition (NOR) and persistence of foot-shock avoidance (IA) memory. Treatment of 5 months-old Tg rats with V restored LTM expression of NOR (Colettis et al., SAN 2023).
V-treatment of elderly Tg and wild type (wt) 15 months-old rats by i.c.v. infusion was assessed in exploratory behavior (OF), NOR and IA task performance two months later. Tg animals showed NOR-STM recovery without significant changes in any of the other tasks/memories. However, V-treated wt female rats improved their performance for STM and a tendency to rescue LTM in the NOR task, being able to also express persistence in the IA task.
Our results suggest that, although V failed to rescue LTM deficits typical of this Tg AD model at an advanced age and development of the pathology, it was successful to recover capacities in young Tg and in elderly wt females. This represents a significant advance in experimental gene therapy at early AD and in aging.