Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer's Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation.

Clinical symptoms of Alzheimer's Disease (AD) include behavioral alterations and cognitive impairment. These functional phenotypes early occur in triple-transgenic (3xTg-AD) mice. Specifically, behavioral alterations are first detected when mice are at around 2.

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

The intracellular deposition of amyloid-β (Aβ) 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-Aβ single-chain variable fragment (scFv) derived from the antibody bapineuzumab, on amyloid pathology in 5-month-old 3xTg-AD female mice, focusing on intracellular Aβ clearance, neuronal survival, and functional abilities.

Pharmacokinetic parameters and mechanism of action of an efficient anti-Aβ single chain antibody fragment.

The success of the targeting of amyloid-β (Aβ) oligomers through immunotherapy in Alzheimer's disease (AD) mouse models has not been translated into the clinics. The use of single-chain variable fragments (scFvs) has been proposed to prevent the potential severe effects of full-length mAbs by precluding crystallizable fraction-mediated microglia activation. The efficacy of scFv-h3D6, a bapineuzumab-derived anti-Aβ scFv, has been extensively proven.

Differential effects of apoE and apoJ mimetic peptides on the action of an anti-Aβ scFv in 3xTg-AD mice.

Anti-Aβ immunotherapy has emerged as a promising approach to treat Alzheimer's disease (AD). The single-chain variable fragment scFv-h3D6 is an anti-Aβ antibody fragment that lacks the Fc region, which is associated with the induction of microglial reactivity by the full-length monoclonal antibody bapineuzumab. ScFv-h3D6 was previously shown to restore the levels of apolipoprotein E (apoE) and apolipoprotein J (apoJ) in a triple-transgenic-AD (3xTg-AD) mouse model.

Production of an anti-Aβ antibody fragment in Pichia pastoris and in vitro and in vivo validation of its therapeutic effect.

ScFv-h3D6 has been shown as an efficient therapy in the 3xTg-AD mouse model of Alzheimer's Disease. Because one of the major bottlenecks for the therapeutic uses of proteins produced in Escherichia coli is their potential contamination with endotoxins, LPS were extensively removed by a rather low-efficient, expensive, and time-consuming purification step. In addition, disulfide scrambling is favored in the reducing bacterial cytoplasm albeit the use of reductase deficient strains.

An Intracellular Amyloid-β/AβPP Epitope Correlates with Neurodegeneration in those Neuronal Populations Early Involved in Alzheimer's Disease.

The main histopathological hallmarks of Alzheimer's disease (AD) are the extracellular deposition of neuritic amyloid plaques, composed of amyloid-β (Aβ) peptide, and the intracellular accumulation of neurofibrillary tangles, composed of hyperphosphorylated tau. Both traits are emulated in the 3xTg-AD mouse model. Because the relevance of this model in the bibliography and the main role of Aβ in neuronal impairment, here we have detailed the brain Aβ/AβPP distribution to subsequently quantify cellular density and intracellular burden for specific neuronal populations in the early stages of the disease.

Mouse Models of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool.

Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid β antibody fragment.

The therapeutic potential of scFv-h3D6 has recently been shown in the 3xTg-AD mice. A clear effect on amyloid β (Aβ) oligomers and certain apolipoproteins in the brain was found, but no effect was seen in the cerebellum. Here, cellular vulnerability of the 3xTg-AD cerebellum is described for the first time, together with its protection by scFv-h3D6.