Progression of Alzheimer's disease and effect of scFv‐h3D6 immunotherapy in the 3xTg‐AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy

Alzheimer's disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β‐amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein. In recent years, Aβ‐immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single‐chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv‐h3D6 generated by our research group derives from this monoclonal antibody, which targets the N‐terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils. In this study, 3xTg‐AD mice were intraperitoneally and monthly treated with 100 μg of scFv‐h3D6 (a dose of ~3.3 mg/kg) or PBS, from 5 to 12 months of age (?mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques are widely used in both human and mouse research, allowing to draw an in vivo picture of concrete aspects of the pathology in a non‐invasive manner and allowing to monitor its development across time. Compared with the genetic background, 3xTg‐AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ_1–42 at 12‐mo, and an inflammation process at this age, in both the hippocampus (IL‐6 and mIns) and cortex (IL‐6). In addition, treatment with scFv‐h3D6 partially recovered the values in brain volume, and Aβ, IL‐6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.