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Preventing memory deficit with an AAV vector expressing a single-chain antibody against amyloid β oligomers in animal models of Alzheimers’ disease

Daniela Alejandra Salas

  • CABA,
  • Argentina
  • Daniela Alejandra Salas ¹
  • , Magalí Cercato ¹
  • , Federico Filippin ¹
  • , María Clara Selles ²
  • , Martín Habif ¹
  • , Tomás Gonzalez Garello ¹
  • , Anna Salvetti ³
  • , Alberto Luis Epstein ⁴
  • , William Klein* ⁵
  • , Sergio Ferreira* ²
  • , Diana Alicia Jerusalinsky* ¹
  • , Natalia Colettis. *corresponding authors o patent owners o inventors ¹
  • 1 IBCN (UBA-CONICET), Argentina
  • 2 Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
  • 3 INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France;
  • 4 UMR INSERM U1179-UVSQ, Université de Versailles Saint Quentin en Yvelines, 78180 Montigny le-Bretonneux, France
  • 5 Department of Neurobiology, Northwestern University, Evanston, USA

Amyloid β oligomers (AβO)-induced alterations in synaptic structure and function was proposed to be implicated in early cognitive impairment in Alzheimer’s disease (AD), long before evident neurodegeneration took place. Thus, specifically targeting AβO by immunotherapy could be an alternative for AD treatment. McGill-R-Thy1-APP transgenic rats with human APP bearing the Swedish and Indiana mutations (of familial AD) in homozygous (+/+) condition, was reported to show cognitive deficits at 3 months. Meanwhile, heterozygous (+/-) rat showed a more subtle and slower developing phenotype, though with consistent memory impairment in 4 month old males. We aimed to evaluate the efficacy of an anti-AβO single-chain variable fragment antibody (NUsc1) expressed from an adeno-associated (AAV) viral vector, to prevent that memory impairment. Two month-old (+/-) rats received an ICV injection of that AAV-NUsc1, which drives neuronal expression of NUsc1. After 2 months, long-term memory (LTM) performance was assessed in either injected or not Tg females and males, and their wt littermates. Both Tg and wt females showed similar LTM performance. Instead, Tg males showed LTM deficits, while those vector-treated expressed LTM as wt rats, indicating that AAV-NUsc1 was able to prevent such deficits. Using same AAV-NUsc1 in different mouse AD models we had also shown STM improvement. Therefore, this sort of immunotherapy emerges as a novel promising experimental tool for AD treatment.