Temporal Pattern of Neuroinflammation Associated with a Low Glycemic Index Diet in the 5xFAD Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is associated with brain amyloid‐β (Aβ) peptide accumulation and neuroinflammation. Currants, a low glycemic index dried fruit, and their components display pleiotropic neuroprotective effects in AD. We examined how diet containing 5% Corinthian currant paste (CurD) administered in 1-month-old 5xFAD mice for 1, 3, and 6 months affects Aβ levels and neuroinflammation in comparison to control diet (ConD) or sugar-matched diet containing 3.5% glucose/fructose (GFD). No change in serum glucose or insulin levels was observed among the three groups. CurD administered for 3 months reduced brain Aβ42 levels in male mice as compared to ConD and GFD, but after 6 months, Aβ42 levels were increased in mice both on CurD and GFD compared to ConD. CurD for 3 months also reduced TNFα and IL-1β levels in male and female mouse cortex homogenates compared to ConD and GFD. However, after 6 months, TNFα levels were increased in cortex homogenates of mice both on CurD and GFD as compared to ConD. A similar pattern was observed for TNFα-expressing cells, mostly co-expressing the microglial marker CD11b, in mouse hippocampus. IL-1β levels were similarly increased in the brain of all groups after 6 months. Furthermore, a time dependent decrease of secreted TNFα levels was found in BV2 microglial cells treated with currant phenolic extract as compared to glucose/fructose solution. Overall, our findings suggest that a short-term currant consumption reduces neuroinflammation in 5xFAD mice as compared to sugar-matched or control diet, but longer-term intake of currant or sugar-matched diet enhances neuroinflammation.

Corinthian Currants Promote the Expression of Paraoxonase-1 and Enhance the Antioxidant Status in Serum and Brain of 5xFAD Mouse Model of Alzheimer’s Disease

“…One-month-old 5xFAD mice (6 males and 5 females per group) were fed a typical diet [control (Con) group], a diet supplemented with 5% (w/w) Corinthian currant paste [currant (Cur) group], or a diet containing 1.75% (w/w) glucose/1.75% (w/w) fructose [(G/F) group], that matches the sugar content in currants, for a duration of 1, 3, and 6 months. A previous study from our lab showed that currant consumption by 5xFAD mice for 3 months resulted in lower brain Aβ42 levels in male mice and reduced neuroinflammation in both male and female mice, but further currant consumption for up to 6 months had no beneficial effect [22]. The mice did not exhibit an increased appetite in response to a sweet diet, or hyperglycemia or hypercholesterolemia at any age [22].…”

“…In a previous study conducted in our lab, it was demonstrated that the polar phenolic extract obtained from Corinthian currants displays free-radical-scavenging properties and reduces the oxidative stress triggered by the uptake of Aβ42 by human neuroblastoma SK-N-SH cells [21]. Additionally, consumption of Corinthian currants for one month by the 5xFAD mouse model of AD reduced AD-related pathological features, such as brain Aβ42 levels and neuroinflammation, in the early stages of the disease [22].…”

“…The 5xFAD transgenic mouse model of AD, on a C57BL/6 background, carries and inherits familial AD mutations of human amyloid precursor protein (APP) [Swedish (K670N, M671L), Florida (I716V) and London (V717I)] and presenilin-1 (M146L and L286V) [23,24]. Genotyping of 5xFAD mice was conducted via PCR analysis of tail DNA [22], with the mice maintained in a heterozygous state. The animals were housed under standard conditions (24 • C, 12 h light/dark cycle, lights on at 8:00 a.m.) with access to food and water ad libitum.…”

“…Currant paste was supplied by the Agricultural Cooperatives' Union of Aeghion, Greece. It was prepared as described previously [22,25], using Corinthian currants produced from a special variety of black grape, i.e., Vitis vinifera L., var. Apyrena, originating from the Aeghion (Vostizza) area in the Peloponnese in Southern Greece.…”

“…At four weeks of age, male and female transgenic mice were randomly allocated into nine groups, each receiving one of three types of diet for a duration of 1, 3, and 6 months. This comprised a total of 99 mice, with 6 males and 5 females per diet and time point, as described previously [22]. Specifically, the mice were fed either a standard chow diet; a chow diet enriched with 5% (w/w) currants paste; or a chow diet containing 1.75% (w/w) glucose/1.75% (w/w) fructose, adjusted to match the sugar content in currants [27].…”