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-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.

High-fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner

“…Others have found no hypoperfusion-induced elevation in Aβ levels in 3xTg-AD mice [ 51 ]; however, this was after only 2 months of hypoperfusion suggesting that changes we observed may have emerged at a later time point. While we did not observe an effect of diet on Aβ pathology, others have found that HF diet increases Aβ in 3xTg-AD mice [ 21 , 24 , 25 , 59 ], with some studies showing that this effect is specific to females [ 57 , 58 ]. This may be due to increased Aβ production that can occur in metabolic disease, which is exacerbated when plaques have formed [ 60 ].…”

High fat diet exacerbates cognitive decline in mouse models of Alzheimer’s disease and mixed dementia in a sex-dependent manner

“…Others have found no hypoperfusion-induced elevation in Aβ levels in 3xTg-AD mice (47), however this was after only 2 months of hypoperfusion suggesting that changes we observed may have emerged at a later timepoint. While we did not observe an effect of diet on Aβ levels, others have found that HF diet increases Aβ in 3xTg-AD mice (21,24,25,51), with some studies showing that this effect is specific to females (52,53). We are limited in our interpretation because we cannot confirm that these cells are neurons and the presence of Aβ in different cell types may have different consequences for pathology.…”

“…While further sex differences in dementia pathology may develop with age, increased Aβ and astrogliosis in females supports the heightened sensitivity of females to AD/MxD and may underlie the wider array of cognitive deficits in females. (52,53) In addition to AD pathology, we also assessed the degree of chronic cerebral hypoperfusion. We found that unilateral carotid artery occlusion surgery (MxD mice) caused deficits in cerebral blood flow in the cortical surface that persisted 4 months after surgery.…”

“…Intraneuronal Aβ has been observed in 3xTg-AD mice beginning at 4 months of age (54,55) and frequently appears in neurons that contain neurofibrillary tangles (56). Others have found increased Aβ levels in female 3xTg-AD mice (21,34,50,52,53,57) as well as increased Aβ positive cell counts in the dorsal hippocampus (38). While further sex differences in dementia pathology may develop with age, increased Aβ and astrogliosis in females supports the heightened sensitivity of females to AD/MxD and may underlie the wider array of cognitive deficits in females.…”

Translational response to mitochondrial stresses is orchestrated by tRNA modifications

“…Loss of tRNA-Q also led to the downregulation of serotonin, possibly through the tetrahydrobiopterin (BH4) pathway(Choi et al, 2006; Fanet et al, 2021a; Rakovich et al, 2011). Dysregulation of the BH4 pathway can impact mitochondrial function(Choi et al, 2006) and was linked to neurodegenerative diseases(Aziz et al, 1983; Choi et al, 2006; Fanet et al, 2021b; Foxton et al, 2007). Such metabolic connection between BH4 pathway and tRNA-Q could be a potential explanation of the phenotype observed in the work by Cirzi et al(Cirzi et al, 2023) and can be an interesting link between tRNA-Q and neurodegenerative diseases.…”