Efficacy and safety of A-beta immunotherapy in a mouse model of AlzheimerÔÇÖs Disease

2018 edition

Alejandro R. Roda

Alzheimer Disease (AD) is a progressive neuropsychiatric disorder characterized by memory loss and behavioral abnormalities. Although its etiology is not clear yet, it is well-known that its main histological features are the extracellular deposits of amyloid plaques, composed of the amyloid-beta (A╬▓) peptide, and the intracellular accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau protein. Because soluble A╬▓ oligomers are thought to be the species inducing neural dysfunction, A╬▓-immunotherapy has emerged as a new hope to treat AD. However, several phase III clinical trials have failed as severe adverse effects, mainly Fc-dependent glia over-activation, occurred. Our research group developed scFv-h3D6, a bapineuzumab derivative, and demonstrated its ability to reduce A╬▓ load and to protect from neuron loss in the 3xTg-AD mouse model of AD. Moreover, an elongated variant (scFv-h3D6-EL) with increased thermodynamic stability was designed. Our previous results show that a single intraperitoneal dose of 100 ┬Ág of scFv-h3D6 wild-type ameliorates early cognitive impairment, as assessed by the Morris Water Maze test; but does not reduce the anxious-like behavior, as quantified by the Open Field test. Interestingly, no glial over-activation was detected in this preliminary study. However, the treatment with the scFv-h3D6-EL variant does not ameliorate the behavioral deficits, even thought it shown more efficient in cell cultures. This differential behavior could be related with different pharmacokinetic properties.