Abstract
Familial Amyloidotic Polyneuropathy (FAP) is a disorder characterized by the extracellular deposition of fibrillar Transthyretin (TTR) amyloid, with a special involvement of the peripheral nerve. We had previously shown that doxycycline administered for 3 months at 40 mg/Kg/ml in the drinking water, was capable of removing TTR amyloid deposits present in stomachs of old TTR-V30M transgenic mice; the removal was accompanied by a decrease in extracellular matrix remodeling proteins that accompany fibrillar deposition, but not of non-fibrillar TTR deposition and/or markers associated with pre-fibrillar deposits. On the other hand, Tauroursodeoxycholic acid (TUDCA), a biliary acid, administrated to the same mouse model was shown to be effective at lowering deposited non-fibrillar TTR, as well as the levels of markers associated with pre-fibrillar TTR, but only at young ages.In the present work we evaluated different doxycycline administration schemes, including different periods of treatment, different dosages and different FAP TTR V30M animal models. Evaluation included CR staining, immunohistochemistry for TTR, metalloproteinase 9 (MMP-9) and serum amyloid P component (SAP). We determined that a minimum period of 15 days of treatment with a 8 mg/Kg/day dosage resulted in fibril removal. The possibility of intermittent treatments was also assessed and a maximum period of 15 days of suspension was determined to maintain tissues amyloid-free. Combined cycled doxycycline and TUDCA administration to mice with amyloid deposition, using two different concentrations of both drugs, was more effective than either individual doxycycline or TUDCA, in significantly lowering TTR deposition and associated tissue markers. The observed synergistic effect of doxycycline/TUDCA in the range of human tolerable quantities, in the transgenic TTR mice models prompts their application in FAP, particularly in the early stages of disease.
Highlights
Familial Amyloid Polyneuropathy (FAP) is characterized by the deposition of Transthyretin (TTR) amyloid fibrils in several organs, with special involvement of the peripheral nerve
Different doxycycline periods in the TTR/HSF model To address the importance of doxycycline as a TTR fibril disrupter and its use in future therapeutic approaches, we tested the initial described dosage (40 mg/Kg/day) in the TTR/HSF mice and decreased the period of treatment to 1 month
As previously reported [11], Congo red (CR) staining is limited to very small and restricted areas, whereas MMP-9 staining visualized, is usually either positive or negative; in both cases we did not proceed to quantitative analysis, and instead we show the results as a percentage of positive relative to the total number of analyzed cases
Summary
Familial Amyloid Polyneuropathy (FAP) is characterized by the deposition of Transthyretin (TTR) amyloid fibrils in several organs, with special involvement of the peripheral nerve. A number of models have been created for FAP, including mice carrying the most prevalent TTR mutation, V30M, under the control of different promoters [2,3], and a highly amyloidogenic TTR variant, L55P [4]. The characterization of these models revealed early presence of non-fibrillar TTR that with aging evolved to TTR amyloid deposits [4], mimicking the human pathological characteristics, except for the lack of deposits in the peripheral nerve. Deposition did not occur in the brain and spinal cord; a significant decrease in unmyelinated fibers occurred when fibrillar material was deposited in nerve [5]
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