Aim: Decrease in adult neurogenesis has been described to correlate with Alzheimer’s disease (AD) progression, and we have previously demonstrated a causal link between Amyloid-beta oligomers (AβOs) accumulation in adult neural stem cells (NSCs) and reduced subventricular zone (SVZ) neurogenesis in AD Tg2576 mouse model at pre-symptomatic stage. Here we investigated if AβOs targeting in the dentate gyrus of AD mice, both at pre-symptomatic and symptomatic stage, can rescue adult hippocampal neurogenesis (AHN) and recover AD-related memory deficits. Methods: Using a disease modifying gene-therapy approach, we perform AβOs targeting in Tg2576 hippocampal progenitors both in vitro and in vivo, through lentiviral delivery ofscFvA13KDEL anti-AβOs intrabody. We evaluated the rescue of AHN and we performed behavioural tests to evaluate cognitive improvement correlated to AHN (Fear Conditioning, Pattern Separation, Social Novelty and Social Memory).Results: in vitro scFvA13KDEL intrabody expression rescued deficits in proliferation and differentiation of AD-hippocampal progenitors. Also in vivo, lentiviral delivery of scFvA13KDEL in the dentate gyrus of Tg2576 mice rescued AHN, increased dendritic length and ramification of granule neurons and improved memory performance in behavioral tasks. Conclusions: These data indicate neurogenesis as a model of AD deficits triggered by intracellular AβOs and provide AβOs gene-immunotargeting exploitable as an innovative therapeutic intervention to counteract disease onset and progression.(supported by #NGEU and founded by MUR, NRRP, project MNESYS - PE0000006 – A Multiscale Integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).