Altered Cholesterol Ester Cycle in Skin Fibroblasts from Patients with Alzheimer's Disease

Pani, Alessandra; Dessı̀, Sandra; Diaz, Giacomo; Colla, Paolo La; Abete, Claudia; Mulas, Claudia; Angius, Fabrizio; Cannas, M. Dolores; Orrú, Christina D.; Cocco, Pier Luigi; Mandas, Antonella; Putzu, P.; Laurenzana, Anna; Cellai, Cristina; Costanza, Antonio Mitidieri; Bavazzano, A.; Mocali, Alessandra; Paoletti, Francesco

doi:10.3233/jad-2009-1193

Cited by 54 publications

(50 citation statements)

References 48 publications

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“…Alternatively, inadequate stores of lipids may reduce the capacity to synthesize sufficient cytoplasmic membrane requirements for mitosis completion leading to cytokinetic arrest and aneuploidy (38). Lipid metabolism has also been studied in fibroblasts from AD patients whereby the cholesterol esterification rate was reported to increase after 48 h of cellular tissue culture (P < 0.05) (19). This level of cholesteryl ester synthesis was linked to an expanded cytoplasmic pool of neutral lipid measured using the ORO staining procedure.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Neutral Lipidsmentioning

confidence: 99%

“…Previous studies in both animal and cellular AD models indicated that intracellular cholesterol distribution can regulate b-amyloid (considered the main biomarker of AD) generation in the brain (18). 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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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Previous studies have shown that mild cognitive impairment (MCI) may be reflective of the early stages of more pronounced neurodegenerative disorders such as Alzheimer's disease (AD). There is a need for a minimally invasive and inexpensive diagnostic to identify those who exhibit cellular pathology indicative of MCI and AD risk so that they can be prioritized for primary preventative measures. The hypothesis was that a minimally invasive approach using cytological markers in isolated buccal mucosa cells can be used to identify individuals of both MCI and AD. An automated buccal cell assay was developed using laser scanning cytometry (LSC) to measure buccal cell type ratios, nuclear DNA content and shape, and neutral lipid content of buccal cells from clinically diagnosed AD (n 5 13) and MCI (n 5 13) patients prior to treatment compared to age-and gender-matched controls (n 5 26). DNA content was significantly higher in all cell types in both MCI (P < 0.01) and AD (P < 0.05) compared with controls mainly due to an increase in >2N nuclei. Abnormal nuclear shape (circularity) was significantly increased in transitional cells in MCI (P < 0.001) and AD (P < 0.01) when compared to controls. In contrast, neutral lipid content (as measured by Oil red O "ORO" staining) of buccal cells was significantly lower in the MCI group (P < 0.05) compared with the control group. The ratio of DNA content/ORO in buccal basal cells for both MCI and AD was significantly higher compared to the control group, with ratios for MCI being approximately 2.8-fold greater (P < 0.01) and AD approximately 2.3-fold greater (P < 0.05) than the control group. Furthermore, there was a strong negative correlation between buccal cell DNA content and ORO content in the AD group (r 2 5 0.75, P < 0.0001) but not in MCI or controls. The changes in the buccal cell cytome observed in this study could prove useful as potential biomarkers in identifying individuals with an increased risk of developing MCI and eventually AD. V C 2014 International Society for Advancement of Cytometry

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Section: Discussionmentioning

confidence: 99%

Section: Neutral Lipidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…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.…”

Section: Ea Schon and E Area-gomez / Mam Dysfunction In Ad Pathogementioning

confidence: 99%

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

Schon

Area‐Gómez

2010

JAD

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Abstract. The subcellular localization of presenilin-1 (PS1) and presenilin-2 (PS2), two proteins that, when mutated, cause familial Alzheimer's disease (AD), is controversial. We have discovered that mitochondria-associated membranes (MAM) -a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria -is the predominant subcellular location for PS1 and PS2, and for γ-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-β levels and hyperphosphorylated tau, but also many other features of AD (e.g., altered phospholipid and cholesterol metabolism, aberrant calcium homeostasis, and abnormal mitochondrial dynamics) result from compromised MAM function. The localization of presenilins and γ-secretase in MAM may help reconcile disparate ideas regarding the pathogenesis of AD, under a unifying hypothesis that could explain many features of both sporadic and familial AD, thereby taking AD research in a new and fruitful direction.Keywords: Alzheimer's disease, calcium, cholesterol, endoplasmic reticulum (ER), mitochondria, mitochondria-associated membranes (MAM), phospholipids ALZHEIMER'S DISEASEAlzheimer's disease (AD), the most common late onset neurodegenerative dementing disorder, is characterized by progressive neuronal loss, especially in the hippocampus and cortex [1]. The two main histopathological hallmarks of AD are the accumulation of extracellular neuritic plaques, containing amyloid-β (Aβ), and of neurofibrillary tangles, consisting mainly of hyperphosphorylated forms of the microtubule-associated protein tau [1]. Most AD patients are sporadic (SAD), but three genes have been associated with the familial form (FAD): amyloid-β protein precursor (AβPP), presenilin-1 (PS1), and presenilin-2 (PS2). Clinically, FAD is similar to SAD but has earlier onset. Presenilins are components of the γ-secretase complex (also containing APH1, nicastrin, and PEN2) that, together with β-secretase, processes AβPP to produce Aβ [1]. In the mainstream view, both SAD and FAD arise when AβPP is processed to Aβ, which accumulates in extracellular plaques. Aβ is toxic to cells and the resulting stress promotes tau hyperphosphorylation, leading to the tangles. The overall process has been called the "amyloid cascade" hypothesis [2,3]. This hypothesis reconciles findings from different approaches to the disease and has served as the basis for many key experiments in vivo and in vitro. However, certain questions that are central to understanding the pathogenesis of AD and the processing of Aβ remain unsolved.The first question concerns features of AD that are not obviously linked to plaque or tangle formation. While plaques and tangles are hallmarks of the disease, other apparently unrelated laboratory abnormali-

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“…Peripheral tissue such as skin fibroblasts from familial and sporadic AD has been shown to exhibit a 2-fold increase in the number of trisomy 21 cells when compared to controls [35]. Moreover, an increase in immunostaining of amyloid peptides (Aβ 40 , Aβ 42 ) as well as an imbalance between free cholesterol and cholesterol ester pools have been observed in fibroblasts of AD [37]. The capacity of fibroblasts to spread in culture was also observed to be altered in AD with a decrease of cytosolic free calcium (p<0.001) [38].…”

Section: Peripheral Tissue As Source For Ad Biomarkersmentioning

confidence: 99%

Biomarkers of Alzheimer’s Disease Risk in Peripheral Tissues; Focus on Buccal Cells

François¹,

Leifert²,

Martins³

et al. 2014

CAR

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Alzheimer’s disease (AD) is a progressive degenerative disorder of the brain and is the most common form of dementia. To-date no simple, inexpensive and minimally invasive procedure is available to confirm with certainty the early diagnosis of AD prior to the manifestations of symptoms characteristic of the disease. Therefore, if population screening of individuals is to be performed, more suitable, easily accessible tissues would need to be used for a diagnostic test that would identify those who exhibit cellular pathology indicative of mild cognitive impairment (MCI) and AD risk so that they can be prioritized for primary prevention. This need for minimally invasive tests could be achieved by targeting surrogate tissues, since it is now well recognized that AD is not only a disorder restricted to pathology and biomarkers within the brain. Human buccal cells for instance are accessible in a minimally invasive manner, and exhibit cytological and nuclear morphologies that may be indicative of accelerated ageing or neurodegenerative disorders such as AD. However, to our knowledge there is no review available in the literature covering the biology of buccal cells and their applications in AD biomarker research. Therefore, the aim of this review is to summarize some of the main findings of biomarkers reported for AD in peripheral tissues, with a further focus on the rationale for the use of the buccal mucosa (BM) for biomarkers of AD and the evidence to date of changes exhibited in buccal cells with AD.

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Altered Cholesterol Ester Cycle in Skin Fibroblasts from Patients with Alzheimer's Disease

Cited by 54 publications

References 48 publications

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

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

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

Biomarkers of Alzheimer’s Disease Risk in Peripheral Tissues; Focus on Buccal Cells

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