Single chain antibody against Ab-oligomers improves performance for some memory tasks in elderly rats

MARÍA V. OBERHOLZER; ALEJANDRO JOSIOWICZ; M. CERCATO; MERCEDES OLIVERA; M. E. ALFARO; DIANA JERUSALINSKY

San Luis

Congreso; XXXVIII Reunion Anual de la Sociedad Argentina de Investigacion en Neurociencias; 2023

Sociedad Argentina de Investigacion en Neurociencias

In early stages of Alzheimer's disease (AD) amyloid-β oligomers (AβO) cause synapticimpairment and memory decline as shown in animal models. NUsc1, a single chainvariable-fragment antibody (scFv) that binds a subpopulation of soluble AβOs preventedshort-term memory (STM) deficit in mice models. We developed an Adeno-Associatedvirus-derived vector (V) to express NUsc1 in neurons. The transgenic McGill-R-Thy1-APPrat (Tg) model of AD suffers a progressive amyloid pathology, with cognitive deteriorationaffecting long-term memory (LTM) of object recognition (NOR) and persistence of foot-shock avoidance (IA) memory. Treatment of 3 months-old (mo) Tg rats with V restoredLTM expression of NOR at 5 mo (Colettis et al., SAN 2023).Treatment with V of 15 mo Tg and wild type (wt) rats, by i.c.v. infusion, was assessed inexploratory behavior (OF), NOR and IA task performances, two months later. Tg animalsshowed NOR-STM recovery without significant changes in any of the othertasks/memories. However, these elderly V-treated wt female rats express STM andshowed a tendency to express LTM in the NOR task, being able to show persistence in theIA task.Our results suggest that, although V treatment failed to rescue LTM deficits typical of thisTg AD model at an advanced age and stage of the pathology, it was successful to recovercapacities in younger Tg and in elderly wt females. This represents a significant advance inexperimental gene therapy at early AD and in aging.Supported by P UE 2018 IBCN (CONICET), PICT 2021 00971 (ANPCYT/FONCYT). UBACYT 201820020220200160BA