Combined Treatment with a BACE Inhibitor and Anti-Aβ Antibody Gantenerumab Enhances Amyloid Reduction in APP_LondonMice

Abstract

Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-A␤ peptide antibodies and secretase inhibitors. Most anti-A␤ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of A␤. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APP London transgenic mice that received treatment with anti-A␤ antibody gantenerumab and BACE inhibitor RO5508887, either as mono-or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain A␤ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of preexisting amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time-and dose-dependent decrease in CSF A␤, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.

The DIAN‐TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model

“…Preclinical data suggest combining therapeutics targeting the amyloid cascade (anti-Aβ and BACEi) significantly enhances reduction of amyloid load and plaque number beyond either monotherapy alone (66, 67). The existing and NexGen arms will be testing individual therapeutics that are a possible first combination (68-71), and the DIAN-TU trial platform’s multiple monotherapies and pooled placebo allow an opportunity to test combinations alongside monotherapy.…”

The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials

“…These combinations may be multiple mechanisms to lower Aβ burden, such as a BACE inhibitor to decrease the production of Aβ 1-42 monomer combined with an antibody that targets aggregated forms of Aβ. Recent animal studies suggest that these approaches might be synergistic in decreasing Aβ, and may have the added benefit in humans of allowing lower doses of each therapeutic to avoid treatment associated adverse events (Jacobsen et al, 2014). Ultimately, it would be ideal to combine anti-Aβ and anti-Tau treatments, particularly in early symptomatic patients.…”

Picosecond pulsed infrared laser tuned to amide I band dissociates polyglutamine fibrils in cells

“…For example, SCA type 1 (SCA1) is caused by ataxin-1 protein (ATXN1) with an abnormally expanded polyglutamine stretch and is characterized by neurodegeneration in a wide range of the central and the peripheral nervous systems (reviewed in [2]). Since amyloid fibrils are believed to be toxic forms, reduction of those fibrils is theoretically a major target for biochemical treatments against neurodegenerative disorders [3]. However, no effective drugs for polyglutamine diseases have been explored using biochemical approaches.…”