234 | Memory Recovery through Aβ-Oligomers Selective Gene-Immuno-Therapy in an Alzheimer’s Disease Rat Model at an Early Stage

Neurochemistry and Neuropharmacology

Author: Natalia Colettis | Email: nataliacolettis@gmail.com

Natalia Claudia Colettis , Maria Victoria Oberholzer , Martin Habif , Daniela Alejandra Salas , William Klein , Adriano Sebollela , Sergio Ferreira , Diana Alicia Jerusalinsky

1° LaNyN, IBCN, School of Medicine, UBA, Argentina.
2° Department of Neurobiology, Northwestern University, Evanston, IL 60201, USA.
3° Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto 14049-900, Brazil.
4° Medical Biochemistry Institute & Biophysics Carlos Chagas Filho Institute, UFRJ; Brazil.

β-Amyloid oligomers (AβOs) were reported as early contributing to synaptic impairment and memory deficits in animal models of Alzheimer’s Disease (AD). A single-chain antibody fragment NUsc1, selectively target a subpopulation of AβOs and rescued short-term memory (STM) in mice models. To neutralize AβOs and enhance therapeutic efficacy, we developed an Adeno-Associated virus-derived vector for expressing NUsc1 (V) in the brain.
The McGill-R-Thy1-hAPP heterozygous transgenic (Tg+/–) rat model of AD displays progressive amyloid pathology, impairing the formation/recall of novel object recognition (NOR) long-term memory (LTM).
We evaluated if early V treatment could rescue NOR LTM in (Tg+/–) rats. Both Tg and wild-type (wt) male rats 10-12 weeks old, were i.c.v. infused with V or saline (control).
After two months, exploration to an open field (OF), new object discrimination and recognition (NOR) and LTM were assessed. Both V-treated and control, wt and Tg+/– rats showed similar exploratory behavior and habituation to the OF. Tg+/– rats failed to express LTM for NOR, whereas prior V treatment restored this capacity
Current AD therapies underutilize genetic tools. Unlike the already approved ADUCANUMAB and LECANEMAB, expensive antibodies targeting higher-order of Aβ aggregates, V offers a viable, accessible advancement in vector-mediated immunotherapy, enabling sustained scFv NUsc1 neuronal expression to neutralize toxic AβOs.