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- W3199384523 abstract "Alzheimer’s disease (AD) is the most common form ofdementia in the elderly and is marked by extraneuronal betaAmyloid (Aβ) plaques and intraneuronal tangles of abnormallyphosphorylated Tau (Neurofibrillary Tangles or NFTs) in the brain.Abnormally phosphorylated tau and NFTs can cause a separate classof neurodegenerative conditions known as tauopathies. Sustainedneuroinflammation accompanies pathogenesis in most of thesediseases including AD, and is marked by elevated cytokines,chemokines and gliosis in the brain. Interleukin 1 (IL-1), a majorproinflammatory cytokine was found to be specifically elevated inAD and Down’s syndrome brains. IL-1 was proposed to form acytokine cycle with Aβ that once turned on, drives AD pathology. Weset out to obtain direct evidence for the role of sustainedupregulation of Interleukin- 1β (IL-1β) in regulating both amyloidand tau pathology using the triple transgenic mouse model ofAlzheimer’s disease (3xTgAD mice), which demonstrate both plaquesand tangles with age. To this end we made use of an induciblemurine model of sustained IL-1β overexpression developed in ourlaboratory. 3xTgAD/IL-1βXAT mice demonstrated a 4-6-fold elevationin phospho-tau pathology despite a 70-80% reduction in amyloidburden after one and three months of IL-1β overexpression.3xTgAD/IL-1βXAT mice also showed upregulated Glycogen SynthaseKinase β (GSK3β) and p38 Mitogen Activated Protein Kinase(p38MAPK), both potential tau kinases, after one month of IL-1βoverexpression. To avoid any confounds arising from a transgenicmodel overexpressing both amyloid and tau, we overexpressed IL-1βin JNPL3 mice, which overexpress human tau with the P301Lmutation. JNPL3/IL-1βXAT mice demonstrated a similar increase inphospho-tau pathology after one and three months of IL-1βoverexpression without changing the expression of transgenic tau.Suppressing the production of prostaglandin E2 by treatingJNPL3/IL-1βXAT mice with SC560, a selective COX-1 inhibitorreversed the IL-1β mediated exacerbation of tau pathology.Therefore, we found direct evidence suggesting that IL-1β mediatedneuroinflammation exacerbates tau pathology, and reducingneuroinflammation by targeting COX-1 can have therapeuticadvantages in tauopathies. Our studies in the 3xTgAD mice alsodemonstrate that neuroinflammation can be a doubleedged sword inAlzheimer’s and immunomodulatory therapies in AD need to beapproached cautiously." @default.
- W3199384523 created "2021-09-27" @default.
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- W3199384523 date "2014-01-01" @default.
- W3199384523 modified "2023-10-17" @default.
- W3199384523 title "The Effect of Sustained Overexpression of Interleukin-1βon Pathology in Murine Models of Alzheimer’s disease andTauopathy" @default.
- W3199384523 hasPublicationYear "2014" @default.
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