Accumulation of neutral lipids in peripheral blood mononuclear cells as a distinctive trait of Alzheimer patients and asymptomatic subjects at risk of disease

Abstract

BackgroundAlzheimer's disease is the most common progressive neurodegenerative disease. In recent years, numerous progresses in the discovery of novel Alzheimer's disease molecular biomarkers in brain as well as in biological fluids have been made. Among them, those involving lipid metabolism are emerging as potential candidates. In particular, an accumulation of neutral lipids was recently found by us in skin fibroblasts from Alzheimer's disease patients. Therefore, with the aim to assess whether peripheral alterations in cholesterol homeostasis might be relevant in Alzheimer's disease development and progression, in the present study we analyzed lipid metabolism in plasma and peripheral blood mononuclear cells from Alzheimer's disease patients and from their first-degree relatives.MethodsBlood samples were obtained from 93 patients with probable Alzheimer's disease and from 91 of their first-degree relatives. As controls we utilized 57, cognitively normal, over-65 year-old volunteers and 113 blood donors aged 21-66 years, respectively. Data are reported as mean ± standard error. Statistical calculations were performed using the statistical analysis software Origin 8.0 version. Data analysis was done using the Student t-test and the Pearson test.ResultsData reported here show high neutral lipid levels and increased ACAT-1 protein in about 85% of peripheral blood mononuclear cells freshly isolated (ex vivo) from patients with probable sporadic Alzheimer's disease compared to about 7% of cognitively normal age-matched controls. A significant reduction in high density lipoprotein-cholesterol levels in plasma from Alzheimer's disease blood samples was also observed. Additionally, correlation analyses reveal a negative correlation between high density lipoprotein-cholesterol and cognitive capacity, as determined by Mini Mental State Examination, as well as between high density lipoprotein-cholesterol and neutral lipid accumulation. We observed great variability in the neutral lipid-peripheral blood mononuclear cells data and in plasma lipid analysis of the subjects enrolled as Alzheimer's disease-first-degree relatives. However, about 30% of them tend to display a peripheral metabolic cholesterol pattern similar to that exhibited by Alzheimer's disease patients.ConclusionWe suggest that neutral lipid-peripheral blood mononuclear cells and plasma high density lipoprotein-cholesterol determinations might be of interest to outline a distinctive metabolic profile applying to both Alzheimer's disease patients and asymptomatic subjects at higher risk of disease.

Altered cytological parameters in buccal cells from individuals with mild cognitive impairment and Alzheimer's disease

“…ORO is a lysochrome fat-soluble dye which has been used for demonstrating the presence of neutral lipids such as cholesteryl esters and triglycerides in cells (19,20). Upon staining, the neutral lipids appear as bright red spots in the cytoplasm.…”

“…A recent study showed that skin fibroblasts from patients with a diagnosis of probable sporadic AD display an imbalance between free cholesterol and cholesterol ester pools (19). Furthermore, Oil Red O (ORO) staining (indicative of accumulation of neutral lipids) was used to demonstrate higher levels of neutral lipids in isolated peripheral blood mononuclear cells of probable AD patients (20). Since there is a lack of data available on accumulation of neutral lipids within buccal cells in vivo, this parameter was also investigated in healthy controls and individuals diagnosed with MCI and AD.…”

Is Alzheimer's Disease a Disorder of Mitochondria-Associated Membranes?

“…Importantly, patients with AD have elevated circulating cholesterol [4,98], and ACAT1 is elevated in the blood [99] and in fibroblasts [100] from AD patients, but the reason for these observations is currently unclear. We suggest that altered communication between the MAM and mitochondria in AD results in increased ACAT1 activity, thereby affecting circulating cholesterol levels and Aβ production.…”

Abnormal Lipid Accumulation and Cluster Formation of Naive Peripheral Blood Mononuclear Cells: A Useful Tool for Early Detection of Central Nervous System Damage in Elderly

“…ORO staining was determined as previously described in detail [3]. Briefly, PBMCs were isolated by carefully layering 500 µl of anticoagulated whole blood onto the upper layer of an equal amount of Ficoll, which were put into 1.5 mL Eppendorf tubes.…”

“…This makes it important to find appropriate diagnostic methods for the primary care setting [1]. We previously reported that freshly isolated (naïve) peripheral blood mononuclear cells (PBMCs) from Alzheimer's disease (AD) affected patients and some of their first-degree relatives are characterized by alterations in cholesterol ester (CE) metabolism, leading to an accumulation of neutral lipids (NLs) in their cytoplasm [3,4]. We suggested that changes in NL content in the PBMCs may reflect altered cholesterol metabolism in the brain, which in turn might contribute to AD pathogenesis.…”