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Tetrahydrobiopterin improves recognition memory in the triple-transgenic mouse model of Alzheimer’s disease, without altering amyloid-β and tau pathologies

Abstract : *Background: Alzheimer's disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized. *Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in the triple-transgenic mouse model of AD (3xTg-AD), a model of age-related tau and amyloid-beta (A beta) neuropathologies associated with behavior impairment. *Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat - CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days. *Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3 xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on A beta and tau neuropathologies. *Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic deficits accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.
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https://hal.inrae.fr/hal-03279728
Contributor : Sylvie Vancassel <>
Submitted on : Tuesday, July 6, 2021 - 4:33:17 PM
Last modification on : Wednesday, September 8, 2021 - 3:34:11 AM

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Distributed under a Creative Commons Attribution - NonCommercial 4.0 International License

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Hortense Fanet, Marine Tournissac, Manon Leclerc, Vicky Caron, Cyntia Tremblay, et al.. Tetrahydrobiopterin improves recognition memory in the triple-transgenic mouse model of Alzheimer’s disease, without altering amyloid-β and tau pathologies. Journal of Alzheimer's Disease, IOS Press, 2021, 79 (2), pp.709-727. ⟨10.3233/JAD-200637⟩. ⟨hal-03279728⟩

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