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[P1–203]: C9ORF72 DIPEPTIDE REPEAT PROTEINS DISRUPT NUCLEOCYTOPLASMIC TRANSPORT
Author(s) -
Ryan Sarah,
Rollinson Sara,
Callister Janis Bennion,
Hobbs Eleanor,
PickeringBrown Stuart
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.023
Subject(s) - c9orf72 , trinucleotide repeat expansion , neurodegeneration , frontotemporal dementia , amyotrophic lateral sclerosis , biology , translation (biology) , coding region , rna , gene , genetics , neuroscience , disease , medicine , dementia , messenger rna , pathology , allele
Background:Pathological aggregations of tau and amyloid beta proteins are the hallmarks of Alzheimer’s disease. Previous work from our group has shown Abl-selective tyrosine kinase inhibitors stimulate beclin-mediated autophagy and promote clearance of neurodegenerative proteins. Specifically, the drugs nilotinib and bosutinib decrease levels of pathological proteins and reverse motor and cognitive decline in mouse models of neurodegenerative disease. Further, we have shown pazopanib, an FDA-approved inhibitor of the tyrosine kinases VEGFR, PDGFRa, PDGFRb, and c-KIT, penetrates the blood-brain barrier and decreases p-tau levels in TauP301L mice. These experiments aim to confirm and expand upon the initial findings as well as determine the effects of pazopanib on amyloid beta in 3x-APP mice. Methods:Male and female TauP301L, 3x-APP, and non-transgenic littermates approximately 12-17 months old were treated with 5mg/kg pazopanib (roughly half the clinically-used dose) or vehicle (DMSO) intraperitoneally (IP) for 3-4 weeks. Phosphorylated tau levels were measured by Western blot and enzyme-linked immunosorbent assay in brain homogenates, and immunohistochemistry in 20mm brain sections, fixed in 4% paraformaldehyde. Serum was collected to assess kidney and liver function. Ab levels and inflammation were measured using MILLIPLEX ELISA. Autophagy markers were measured via Western blot. Results: Pazopanib treatment does not alter weight, liver (ALT), or kidney injury markers in TauP301L and 3x-APP mouse cohorts. Pazopanib significantly reduces levels of p-tau (T181, T231) in TauP301L mice. Further, brain levels of beclin-1 and p-mTOR/mTOR were unchanged. In 3x-APP mice, treatment does not alter Ab40 or Ab42levels. However, pazopanib significantly reverses levels of IP-10, MIP-1a, MIP-1b, and RANTES toward control levels. Conclusions: Pazopanib (5mg/kg) appears to be a safe, well-tolerated drug that significantly reduces p-tau levels in TauP301L mice in a manner likely independent of beclin or mTOR-mediated autophagy and reverses inflammation in 3x-APP mice. Future studies aim to determine which specific tyrosine kinase target(s) is complicit in p-tau clearance.