Treatment with scFv-h3D6 Prevented Neuronal Loss and Improved Spatial Memory in Young 3xTg-AD Mice by Reducing the Intracellular Amyloid-β Burden

Gisela Esquerda-Canals, Alejandro R. Roda, Joaquim Martí-Clúa, Laia Montoliu-Gaya, Geovanny Rivera-Hernández, Sandra Villegas

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6 Citations (Scopus)

Abstract

The intracellular deposition of amyloid-beta (A beta) peptides has been described in the brains of both Alzheimer's disease (AD) patients and animal models. A correlation between the intracellular amyloid burden and neurodegeneration has recently been reported in a triple-transgenic AD (3xTg-AD) murine model. In the present study, we assessed the effect of scFv-h3D6, an anti-A beta single-chain variable fragment (scFv) derived from the antibody bapineuzumab, on amyloid pathology in 5-month-old 3xTg-AD female mice, focusing on intracellular A beta clearance, neuronal survival, and functional abilities. We also examined neuroinflammation and the histology of peripheral organ samples to detect any adverse effects. A single intraperitoneal injection of scFv-h3D6 dramatically reduced intracellular A beta burden in the deep layers of the cerebral cortex, pyramidal cells layer of the hippocampus, and basolateral amygdalar nucleus. The treatment prevented neuronal loss in the hippocampus and amygdala, while neither astrogliosis nor microgliosis was induced. Instead, an increase in the size of the white pulp after the treatment indicated that the spleen could be involved in the clearance mechanism. Although the treatment did not ameliorate behavioral and psychological symptoms of dementia-like symptoms, the results of cognitive testing pointed to a noticeable improvement in spatial memory. These findings indicated that the mechanism underlying the therapeutic effect of scFv-h3D6 was the clearance of intracellular A beta with subsequent prevention of neuronal loss and amelioration of cognitive disabilities. The treatment was safe in terms of neuroinflammation and kidney and liver function, whereas some effects on the spleen were observed.

Original languageEnglish
Pages (from-to)1069-1091
Number of pages23
JournalJournal of Alzheimer's Disease
Volume70
Issue number4
DOIs
Publication statusPublished - 1 Jan 2019

Keywords

  • 3xTg-AD
  • A-BETA
  • ACCUMULATION
  • ALZHEIMERS-DISEASE
  • Alzheimer's disease
  • CHAIN VARIABLE FRAGMENT
  • DEPOSITION
  • MOUSE MODELS
  • NEURODEGENERATION
  • PERIPHERAL COMPLEMENT INTERACTIONS
  • TANGLE FORMATION
  • TRIPLE-TRANSGENIC MODEL
  • amyloid-beta
  • immunotherapy
  • scFv

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