Western Diet Induces Impairment of Liver-Brain Axis Accelerating Neuroinflammation and Amyloid Pathology in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is an aging-dependent, irreversible neurodegenerative disorder and the most common cause of dementia. The prevailing AD hypothesis points to the central role of altered cleavage of amyloid precursor protein (APP) and formation of toxic amyloid-β (Aβ) deposits in the brain. The lack of efficient AD treatments stems from incomplete knowledge on AD causes and environmental risk factors. The role of lifestyle factors, including diet, in neurological diseases is now beginning to attract considerable attention. One of them is western diet (WD), which can lead to many serious diseases that develop with age. The aim of the study was to investigate whether WD-derived systemic disturbances may accelerate the brain neuroinflammation and amyloidogenesis at the early stages of AD development. To verify this hypothesis, transgenic mice expressing human APP with AD-causing mutations (APPswe) were fed with WD from the 3rd month of age. These mice were compared to APPswe mice, in which short-term high-grade inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All experimental subgroups of animals were subsequently analyzed at 4-, 8-, and 12-months of age. APPswe mice at 4- and 8-months-old represent earlier pre-plaque stages of AD, while 12-month-old animals represent later stages of AD, with visible amyloid pathology. Already short time of WD feeding induced in 4-month-old animals such brain neuroinflammation events as enhanced astrogliosis, to a level comparable to that induced by the administration of pro-inflammatory LPS, and microglia activation in 8-month-old mice. Also, WD feeding accelerated increased Aβ production, observed already in 8-month-old animals. These brain changes corresponded to diet-induced metabolic disorders, including increased cholesterol level in 4-months of age, and advanced hypercholesterolemia and fatty liver disease in 8-month-old mice. These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD development, and that a healthy, balanced, diet may be one of the most efficient AD prevention methods.

Nutrition, Physical Activity, and Other Lifestyle Factors in the Prevention of Cognitive Decline and Dementia

“…Indeed, the Western dietary pattern has been associated with an increased risk of AD, although the underlying mechanisms are not yet completely clear [64]. In experimental studies, the Western diet enhanced brain inflammation and the production of beta-amyloid protein [65]. Furthermore, the Med-Diet, DASH, and MIND diets reduce middle-age CV risk factors that are also risk factors for AD, including vascular disease, hypertension, stroke, diabetes, and obesity [26,[66][67][68][69][70].…”

Effect of Dietary Soybean Oil Inclusion on Liver-Related Transcription Factors in a Pig Model for Metabolic Diseases

“…Nuthikattu et al identified the ESR1 TF as a DEG modulated by the Western diet when comparing the gene expression between female mice groups with a deficiency on low-density lipoprotein receptor in the hippocampus microvessels fed either a control or occidental diet [23]. According to Wiȩckowska-Gacek et al occidental diet may cause metabolic syndromes and diseases due to several factors, including the low consumption of unsaturated FA [24]. The ESR1 TF (nuclear) participates in several DEG-related mechanisms and effects in our study, inhibiting the RXRA TF and the NED4L DEG and activating other genes such as MAPT, ABT, and ACOX2.…”

“…The detoxifying function is mainly for hazard product degradation and involves β-amyloid peptides (circulating Aβ). Furthermore, some factors such as insulin resistance hinder the detoxification process, leading to an overall increase in the Aβ level [24]. One of the first steps in AD progression refers to the appearance of pathological Aβ peptides.…”

A Critical Review of the Study of Neuroprotective Diets to Reduce Cognitive Decline

“…The Western diet is linked to an increased risk of AD, although the underlying mechanisms are not fully understood. In mouse models, the Western diet accelerated brain inflammation and the production of beta-amyloid protein [ 18 ]. Additionally, the Medi, DASH, and MIND diets reduce middle-age risk factors for AD, including vascular disease, hypertension, stroke, diabetes, and obesity [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”