Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model

Versele, Romain; Corsi, Mariangela; Fuso, Andrea; Sevin, Emmanuel; Businaro, Rita; Gosselet, Fabien; Fénart, Laurence; Candela, Pietra

doi:10.3390/ijms21030934

Cited by 47 publications

(41 citation statements)

References 92 publications

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“…βhB is an HDAC inhibitor [ 94 , 95 ], providing a mechanistic basis for βhB-mediated suppression of CypA-NFκB-MMP9 cascade via an increase in the pathway inhibitor, LRP1, which would also support Aβ clearance. Indeed, βhB was recently shown to increase LRP1 levels in a human BBB model [ 91 ]. Furthermore, βhB inhibits the NFκB component of the pathway by binding GPR109A receptor [ 96 , 97 ], which the Montagne group found was sufficient to protect the BBB in ApoE4 mice [ 21 ].…”

Section: Precision Nutrition Considerationsmentioning

confidence: 99%

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

et al. 2021

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The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.

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Section: Precision Nutrition Considerationsmentioning

confidence: 99%

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

et al. 2021

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“…Other neuroprotective mechanisms that have been highlighted against the development of AD are the reduction of the Amyloid Precursor Protein (APP) production [91] and of Aβ deposition [103]. Moreover, a recent study has shown that in vitro KBs are able to induce Aβ clearance from the brain to blood [127]. According to some evidence, treatment with KD has been also associated with an increase of angiogenesis and capillary density, suggesting that the KBs may support the cognitive processes through an improvement of the cerebral microvascularization [94].…”

Section: Suggested Mechanisms Between Ketogenic Diet and Alzheimer's mentioning

confidence: 99%

Influence of the Mediterranean and Ketogenic Diets on Cognitive Status and Decline: A Narrative Review

et al. 2020

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Alzheimer’s disease (AD) is the most common form of senile dementia, accounting for up to 70% of dementia cases. AD is a slowly progressive disease, which causes global mental deterioration by affecting various cognitive areas. A growing body of evidence has demonstrated that lifestyle habits and nutritional patterns could delay the natural course of the neurodegeneration process. There is no single dietary pattern unequivocally proven to prevent AD. Nevertheless, epidemiological data suggest that by adopting several dietary habits, especially if accompanied with a healthy lifestyle, the negative consequences of AD could potentially be delayed. Alongside with others, two specific eating patterns have been well investigated concerning their potential beneficial effect on cognitive status: the Mediterranean diet (MedDi) and the Ketogenic Diet (KD). Despite the different underlying mechanisms, both of them have demonstrated a fairly profitable role in reducing or delaying cognitive impairment. The aim of the present narrative review is to overview the existing research on the efficacy of MedDi and KD against AD-related cognitive decline, focusing on the proposed protective mechanisms of action. Although the current knowledge on this complex topic does not allow us, at this point, to make exhaustive conclusions, this information could be of help in order to better characterize the possible role of MedDi and KD as nonpharmacological therapies in the treatment of AD and, more generically, of neurodegenerative disorders.

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“…After 6 days of co-culture, the resulting hBLECs express TJ proteins at cell-cell contacts and transporters typically observed in the brain endothelium, maintaining the properties of in vivo BBB for at least 20 days [28], a period during which we performed transport experiments. This model is now widely used to investigate BBB physiology, as well as molecules and cells passage across the BBB [80][81][82][83][84][85]. The loading of the human BBB model with GM1 or OligoGM1, followed by the measure of permeability parameters, provided evidence to consider OligoGM1 as a molecule transported by the paracellular mechanism, and importantly with a rate 20-fold higher then ganglioside GM1 (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

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Maggioni

et al. 2020

IJMS

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Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1 s potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1 s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 • C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1 s pharmacological potential, offering a tangible therapeutic strategy.However, transferring the GM1 neuronal potential from the preclinical models to the clinic depends on its ability to reach the brain structures when administered peripherally. This last aspect is actually severely limited by GM1 s amphiphilicity, which hampers the passage across the blood-brain barrier (BBB) [2,7,8]. This barrier is located at the brain microvessel level and strongly restricts the entry of cells and xenobiotics into the CNS. The BBB anatomical support is the specialized brain endothelial cells of these vessels. These cells do not show any fenestrations and are specifically characterized by the presence of tight junctions (TJ), composed of junctional proteins and TJ-associated proteins. Additionally, these cells express several proteins belonging to the ATP-binding cassette (ABC) transporters family, which act as efflux pumps and play an important role by limiting BBB crossing of several drugs and biological molecules [9,10]. The major efflux pumps expressed at the BBB are P-glycoprotein (P-gp, aka ABCB1), breast cancer resistance protein (BCRP, aka ABCG2), and the multidrug-resistance-associated proteins (MRPs, aka ABCCs).Importantly, the fate of peripherally administered GM1 observed in the rodent models has not been determined in humans, as often the two species display different BBB permeability rates for the same molecule [7,8]. One of the possible explanations for these discrepancies is the species difference recently reported between rodents and human for the expression of several receptors and transporters expressed in the BBB, in...

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Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model

Cited by 47 publications

References 92 publications

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

Influence of the Mediterranean and Ketogenic Diets on Cognitive Status and Decline: A Narrative Review

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

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