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.
Highlights
Cladribine or leustatin (2-chloro-29-deoxyadenosine or 2-CDA) is a synthetic chlorinated analog of deoxyadenosine which interferes with DNA repair resulting in strand breaks and apoptosis [1,2]
Taken 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
Results from RNA profiling studies suggest that deoxycytidine kinase (DCK) levels are high in T cells, B cells and dendritic cells but low in nonhematologic cell types such as liver, brain, lung, heart, skin, kidney and germ cells [7,8], which may have an advantage of reduced adverse events related to these organs for 2-CDA
Summary
Cladribine or leustatin (2-chloro-29-deoxyadenosine or 2-CDA) is a synthetic chlorinated analog of deoxyadenosine which interferes with DNA repair resulting in strand breaks and apoptosis [1,2]. Adenosine deaminase is unable to cleave 2-CDA because of substitution of hydrogen with a chlorine atom at position 2 of the purine ring of deoxyadenosine. Once 2-CDA is taken up by cells through specific nucleotide transporters, it is phosphorylated by deoxycytidine kinase (DCK) through multiple steps resulting in 2chlorodeoxyadenosine 59-triphosphate (2-CdATP), which is the active form [5]. Since both activated and resting lymphocytes have high levels of DCK, 2-CDA accumulates at high levels within lymphocytes making them more vulnerable to cytotoxic effects [6]. Whether long-term administration of 2-CDA can lead to any adverse effects in patients or animal models is not yet clearly known
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