Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer’s disease: Alleviation by pantethine

Abstract

Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer’s disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine.

Long-Term Pantethine Treatment Counteracts Pathologic Gene Dysregulation and Decreases Alzheimer's Disease Pathogenesis in a Transgenic Mouse Model

“…To investigate the effects of pantethine on AD pathology, 1.5 month-old 5xFAD transgenic (Tg thereafter) and wild type (WT thereafter) mice were treated with pantethine for 5.5 months (see materials and methods). In line with our previous data (17), a significant decrease in gliosis and A plaque deposits was observed in treated Tg mice compared to untreated.…”

“…At first, immunohistological analyses of brain sections at the hippocampal level in 7-month-old Tg and WT mice ( Fig. 1A) supported our previous results on cultured astrocytes (17). Indeed, in sections immunostained with anti-GFAP and anti-IBA1 antibodies, Tg mice consistently exhibited a higher signal (10-fold and 20-fold increase, respectively) than WT mice (Fig.…”

“…We have previously shown that pantethine is able to protect mice against cerebral malaria by preserving blood brain barrier integrity and by lowering TNF- levels (16). More recently, we demonstrated that pantethine alleviates metabolic dysfunctions, reduces astrogliosis and IL-1 production in primary cultured astrocytes of 5XFAD mice (17). Such beneficial effects were also observed in WT astrocytes treated with A oligomers.…”

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

“…Brain metabolic perturbations have been described in several transgenic AD models. For instance, the disturbances in metabolites of the glycolytic pathway (glucose-6-phosphate and glycerol-3-phosphate) and tricarboxylic acid (TCA) cycle (α-ketoglutarate, fumarate, and succinate) were identified in astrocytes derived from newborn 5xFAD mice [11], and pantethine treatment reduced the extent of metabolic perturbation and decreased the inflammatory processes in these astrocytes, indicating the role of altered brain energetics in the AD pathogenesis; metabolic profile analyses revealed region-specific metabolic changes in the hippocampus, cortex, cerebellum, and olfactory bulbs in APP/PS1 mice [12,13], and metabolomics signatures, including mitochondrial dysfunction and altered energy metabolism indicated by changes in nucleotide, TCA cycle, energy transfer, neurotransmitter, and amino acid metabolic pathways, were identified in APP/PS1 mice [14]; in addition, significant changes in metabolite compositions, including accumulation of fatty acids, alterations in phospholipids and acylcarnitines related to neural membrane degradation, and impaired energy management, were observed in the hippocampus and cortex in APP/PS1 mice [13]. Because the metabolic pathways are conserved through evolution [15,16], the metabolic signatures identified in AD mouse models could be directly translated into human studies [17].…”

Mitochondrial Function in Alzheimer’s Disease: Focus on Astrocytes

“…For example, in the 5xFAD mouse model, expressing five FAD mutations in genes encoding APP and PSEN1 [58], impairment in energy metabolism and activation status in neonatal astrocytes of transgenic mice was very recently discovered [59]. In addition, an impairment in Aβ uptake and neuronal support was demonstrated in old 5xFAD astrocytes [60].…”