Hypercholesterolemia in rats impairs the cholinergic system and leads to memory deficits

Abstract

Alzheimer's disease (AD) is a chronic brain disorder characterized by cognitive impairment, cholinergic dysfunction, inflammation, tau and beta-amyloid pathology and vascular damage. Recent studies have shown, that high cholesterol levels are linked to the pathology of AD. The aim of our present work was to study the effects of hypercholesterolemia in adult rats. Five months after 5% cholesterol-enriched diet plasma cholesterol levels and total weight were significantly enhanced compared to controls. Spatial memory was studied in an 8-arm radial maze and cholesterol-treated rats showed an impaired learning and long-term memory. Hypercholesterolemia significantly reduced the number of cholinergic neurons in the basal nucleus of Meynert and decreased acetylcholine levels in the cortex. Nerve growth factor was only slightly enhanced in the cortex of cholesterol-treated animals. Levels of amyloid precursor protein, beta-amyloid(1–42), as well as tau and phospho-tau 181 were significantly enhanced in the cortex of cholesterol-fed rats. Hypercholesterolemia markedly increased several cerebral inflammatory markers and enhanced microglial CD11b-like immunoreactivity. Vascular density, stained by RECA-1 was not changed. However, cholesterol induced cortical microbleedings illustrated by intensive anti-rat IgG-positive spots in the cortex. In conclusion, our data demonstrate that hypercholesterolemia in rats caused memory impairment, cholinergic dysfunction, inflammation, enhanced cortical beta-amyloid and tau and microbleedings, all indications, which resemble an AD-like pathology.

Effects of Walnut Polyphenol on Learning and Memory Functions in Hypercholesterolemia Mice

“…In addition, several lines of evidence have confirmed that hypercholesterolemia affects oxidative stress and Aβ in animal and shows some neuropathological changes similar to those seen in memory disorders [8,57]. Epidemiological studies suggest that high level of cholesterol increases Aβ generation and inhibits α-secretase via activation of both β-and γ-secretases and that hypercholesterolemia increases Aβ levels in the brain [58].…”

“…Obesity and hypercholesterolemia and oxidative stress play a pivotal role in the development of learning and memory impairment [4,8,9]. Long-term use of high fat diet or high energy diet could induce obesity and affect serum lipid levels and oxidative stress, which in turn affect learning and memory functions [37,38,39].…”

“…This is supported by studies in vivo, which confirm a potential beneficial protecting effect via inhibiting the cholesterol synthesis and lowering the concentrations of cholesterol against memory impairments [6,7]. However, the exact mechanism of high blood cholesterol induce memory deficits is not known [8]. In addition, oxidative stress has been strongly concerned in the pathophysiology of learning and memory impairment [9].…”

Dietary Cholesterol Protects Anesthesia-Induced Cognitive Deficits in Wistar Rats

“…It has been reported that diet-induced hypercholesterolemia, or high cholesterol, in male Sprague Dawley rats results in impaired learning and memory, reduced survival of NBM (Nucleus Basalis of Meynert) cholinergic neurons, reduced cortical acetylcholine, elevated inflammatory factors, elevated cortical β-amyloid, tau, and phospho-tau 181 and increased presence of small cortical BBB (blood brain barrier) feedings [13].…”

Caffeine blocks cholesterol-enriched diet induced AD-like pathology in rabbits

“…Second, apoE4 is associated with elevated levels of plasma cholesterol [4,5]. Third, elevated levels of plasma cholesterol, independent of APOE genotypes, has been linked to the pathogenesis of sporadic AD [6][7][8][9][10], as supported by epidemiology studies [6,9] as well as experimental studies conducted in AβPP transgenic mice [11,12], in guinea pigs [13], in rabbits [14], and in rats [15].…”