NSC PhD Thesis Defense Seminar: Simantini Ghosh
The Effect of Sustained Overexpression of Interleukin-1Β on Pathology in Murine Models of Alzheimer's Disease and Tauopathy
Thursday, December 12
Alzheimer's disease (AD) is the most common form of dementia in the elderly and is marked by extraneuronal beta Amyloid (AΒ) plaques and intraneuronal tangles of abnormally phosphorylated Tau (Neurofibrillary Tangles or NFTs) in the brain. Abnormally phosphorylated tau and NFTs can cause a separate class of neurodegenerative conditions known as tauopathies. Sustained neuroinflammation accompanies pathogenesis in most of these diseases including AD, and is marked by elevated cytokines, chemokines and gliosis in the brain. Interleukin 1 (IL-1), a major proinflammatory cytokine was found to be specifically elevated in AD and Down's syndrome brains. IL-1 was proposed to form a cytokine cycle with AΒ that once turned on, drives AD pathology. We set out to obtain direct evidence for the role of sustained upregulation of Interleukin-1Β (IL-1Β) in regulating both amyloid and tau pathology using the triple transgenic mouse model of Alzheimer's disease (3xTgAD mice), which demonstrate both plaques and tangles with age. To this end we made use of an inducible murine model of sustained IL-1Β overexpression developed in our laboratory. 3xTgAD/IL-1ΒXAT mice demonstrated a 4-6-fold elevation in phospho-tau pathology despite a 70-80% reduction in amyloid burden after one and three months of IL-1Β overexpression. 3xTgAD/IL-1ΒXAT mice also showed upregulated Glycogen Synthase Kinase Β (GSK3Β) and p38 Mitogen Activated Protein Kinase (p38MAPK), both potential tau kinases, after one month of IL-1Β overexpression. To avoid any confounds arising from a transgenic model overexpressing both amyloid and tau, we overexpressed IL-1Β in JNPL3 mice, which overexpress human tau with the P301L mutation. JNPL3/IL-1ΒXAT mice demonstrated a similar increase in phospho-tau pathology after one and three months of IL-1Β overexpression without changing the expression of transgenic tau. Suppressing the production of prostaglandin E2 by treating JNPL3/IL-1ΒXAT mice with SC560, a selective COX1 inhibitor reversed the IL-1Β mediated exacerbation of tau pathology. Therefore, we found direct evidence suggesting that IL-1Β mediated neuroinflammation exacerbates tau pathology, and reducing neuroinflammation by targeting COX1 can have therapeutic advantages in tauopathies. Our studies in the 3xTgAD mice also demonstrate that neuroinflammation can be a double-edged sword in Alzheimer's and immunomodulatory therapies in AD need to be approached cautiously.
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