TARGETING INTRACELLULAR A-ΒETA OLIGOMERS PROMOTES NEUROGENESIS-DEPENDENT RESCUE OF HIPPOCAMPAL FUNCTION AND MEMORY IN AN ALZHEIMER'S DISEASE MOUSE MODEL

Background: Adult hippocampal neurogenesis (AHN) is critically involved in memory processing and is progressively impaired in Alzheimer’s disease (AD). We previously showed that intracellular amyloid-β oligomers (AβOs) accumulate in adult neural stem cells (aNsc) and causally contribute to defective subventricular zone neurogenesis at early stages of AD. Whether selective targeting of AβOs within the hippocampal niche can restore AHN and cognitive function across disease stages remains unclear.
Methods: We used a disease modifying gene-therapy approach to target AβOs in hippocampal progenitors of Tg2576 mice, both in vitro and in vivo, through lentiviral delivery of the anti-AβOs intrabody scFvA13KDEL (A13KDEL). A13KDEL was expressed in the dentate gyrus at pre-symptomatic and symptomatic stages. AHN was assessed by analysis of progenitor proliferation and neuronal differentiation, while dendritic architecture of granule neurons was evaluated by morphological reconstruction. Cognitive performance was examined using hippocampus-dependent behavioral tasks.
Results: A13KDEL expression rescued neurogenesis defects in AD model both in vitro and in vivo: targeting of AβOs increased AHN, promoted dendritic growth and complexity of granule neurons, and improved cognitive performance at both early and advanced stages of pathology. Notably, pharmacological suppression of cell proliferation abolished the A13KDEL-induced cognitive improvement, indicating that memory rescue driven by intrabody-based targeting of intracellular AβOs requires intact AHN.
Conclusions: Our findings identify intracellular AβOs as key regulators of neurogenesis-dependent cognitive dysfunction in AD and support intrabody-based targeting of AβOs as a promising therapeutic strategy to counteract disease progression.
#NGEU/MUR/NRRP/MNESYS–PE0000006-DN1553-11/10/2022;FOE: CNR-EBRI,2022/2024