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Amyloid-β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset.

Neurobiology of aging (2014-12-03)
Pedro A Dionísio, Joana D Amaral, Maria F Ribeiro, Adrian C Lo, Rudi D'Hooge, Cecília M P Rodrigues
ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder hallmarked by the accumulation of extracellular amyloid-β (Aβ) peptide and intraneuronal hyperphosphorylated tau, as well as chronic neuroinflammation. Tauroursodeoxycholic acid (TUDCA) is an endogenous anti-apoptotic bile acid with potent neuroprotective properties in several experimental models of AD. We have previously reported the therapeutic efficacy of TUDCA treatment before amyloid plaque deposition in APP/PS1 double-transgenic mice. In the present study, we evaluated the protective effects of TUDCA when administrated after the onset of amyloid pathology. APP/PS1 transgenic mice with 7 months of age were injected intraperitoneally with TUDCA (500 mg/kg) every 3 days for 3 months. TUDCA treatment significantly attenuated Aβ deposition in the brain, with a concomitant decrease in Aβ₁₋₄₀ and Aβ₁₋₄₂ levels. The amyloidogenic processing of amyloid precursor protein was also reduced, indicating that TUDCA interferes with Aβ production. In addition, TUDCA abrogated GSK3β hyperactivity, which is highly implicated in tau hyperphosphorylation and glial activation. This effect was likely dependent on the specific activation of the upstream kinase, Akt. Finally, TUDCA treatment decreased glial activation and reduced proinflammatory cytokine messenger RNA expression, while partially rescuing synaptic loss. Overall, our results suggest that TUDCA is a promising therapeutic strategy not only for prevention but also for treatment of AD after disease onset.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Thioflavin T, used as stain for amyloid
Sigma-Aldrich
Tris(tert-butoxy)silanol, 99.999%
Sigma-Aldrich
Tris(tert-butoxy)silanol, packaged for use in deposition systems