Tetrahydrobiopterin Improves Recognition Memory in the Triple-Transgenic Mouse Model of Alzheimer’s Disease, Without Altering Amyloid-β and Tau Pathologies

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-β (Aβ) 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 3xTg-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 Aβ 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.