Chronic Cladribine Administration Increases Amyloid Beta Peptide Generation and Plaque Burden in Mice

Abstract

BackgroundThe clinical uses of 2-chloro-2′-deoxyadenosine (2-CDA) or cladribine which was initially prescribed to patients with hematological and lymphoid cancers is now extended to treat patients with multiple sclerosis (MS). Previous data has shown that 2-CDA has high affinity to the brain and readily passes through the blood brain barrier reaching CSF concentrations 25% of that found in plasma. However, whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known.MethodologyHere we show that exposure of 2-CDA to CHO cells stably expressing wild-type APP751 increased generation and secretion of amyloid β peptide (Aβ) in to the conditioned medium. Interestingly, increased Aβ levels were noticed even at non-toxic concentrations of 2-CDA. Remarkably, chronic treatment of APdE9 mice, a model of Alzheimer's disease with 2-CDA for 60 days increased amyloid plaque burden by more than 1-fold. Increased Aβ generation appears to result from increased turnover of APP as revealed by cycloheximide-chase experiments. Additionally, surface labeling of APP with biotin and immunoprecipitation of surface labeled proteins with anti-biotin antibody also indicated increased APP at the cell surface in 2-CDA treated cells compared to controls. Increased turnover of APP by 2-CDA in turn might be a consequence of decreased protein levels of PIN 1, which is known to regulate cis-trans isomerization and phosphorylation of APP. Most importantly, like many other oncology drugs, 2-CDA administration led to significant delay in acquiring a reward-based learning task in a T maze paradigm.ConclusionsTaken together, these data provide compelling evidence for the first time that chronic 2-CDA administration can increase amyloidogenic processing of APP leading to robustly increased plaque burden which may be responsible for the observed deficits in learning skills. Thus chronic treatment of mice with 2-CDA can have deleterious effects in vivo.

Effects of Huanglian-Jie-Du-Tang and Its Modified Formula on the Modulation of Amyloid-β Precursor Protein Processing in Alzheimer's Disease Models

“…We believe that baicalein treatment augments the abnormal processing of neuronal APP generating amyloidogenic fragments that, upon proteolysis, form Aβ. Similar to our study on the Aβ potentiating effect of baicalein, the anticancer drug cladribine and the proton-pump inhibitor lansoprazole have recently been shown to significantly increase the generation of Aβ and amyloid plaques in cellular and animal models of AD [49], [50]. These Western drugs also significantly and dose dependently increased CTFs and sAPPs, in line with our findings that baicalein, RS and HLJDT mediated increases of APP metabolic products.…”

COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

“…To minimize the variations in sample loading, we normalized the levels of A␤, CTFs, and sAPPs to that of actin. Ab9 antibody (N terminus mAb, epitope A␤1-16) was used to immunoprecipitate A␤, and a combination of 6E10/82E1 antibodies were used for detection (11,17,18). The result revealed a 3-fold increase (p Ͻ 0.001) in A␤ levels and more than a 3-fold increase (p Ͻ 0.001) in the CTF levels upon COPS5 overexpression (Fig.…”

Improvement of Electroacupuncture on APP/PS1 Transgenic Mice in Spatial Learning and Memory Probably due to Expression of Aβ and LRP1 in Hippocampus

“…In addition, the BBB model cultured in vitro by the brain microvascular endothelial cell line has also been used to detect whether A β can be transported through the BBB, and the finding was affirmative [13, 14]. A β is a polar, soluble macromolecular substance [15], and it cannot be freely exchanged between the brain and peripheral blood via free diffusion.…”