Plasma lipids and cholesterol esterification in Alzheimer's disease

Knebl, Janice; DeFazio, Peggy; Mb, Clearfield; Little, Leah A.; McConathy, W. J.; McPherson, Ruth; Ag, Lacko

doi:10.1016/0047-6374(94)90039-6

Cited by 32 publications

(19 citation statements)

References 18 publications

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“…Our data show that HDL-C was significantly higher in AD patients when compared to controls, indicating a lower cardiovascular lipid risk profile in the AD group (table 2). These finding are in accord with our earlier observations obtained with a smaller American cohort [30] that showed higher HDL-C levels in AD patients as compared to controls. However, our results of increased HDL-C levels in AD patients are not in agreement with the findings of Erkinjuntti et al [17], Lehtonen and Luutonen [31] and Mowat et al [32].…”

Section: Discussionsupporting

confidence: 83%

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Evaluation of Serum-Lipid-Related Cardiovascular Risk Factors in Alzheimer’s Disease

Kálmán

Kudchodkar

Murray

et al. 1999

Dement Geriatr Cogn Disord

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There is now sufficient evidence to suggest that cardiovascular pathology and altered lipid metabolism contribute to the development of late-onset Alzheimer’s disease (AD). In the present study, 24 AD patients and 15 controls were assessed for cardiovascular risk based on serum lipid and lipid oxidation parameters. The AD patients appeared to have a more favorable cardiovascular risk profile than the controls based on high-density lipoprotein cholesterol (HDL-C) values. The levels of thiobarbituric-acid-rective substances and the activity of the enzyme paraoxonase (PON) following copper oxidation indicate that female patients may have better protection against serum and perhaps tissue oxidants than males with AD. While the higher HDL-C values indicate lower cardiovascular risk, additional data on oxidized lipid parameters suggest a lower level of protection against serum oxidants in male AD probands.

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Section: Discussionsupporting

confidence: 83%

“…Several reports have appeared in the literature reporting on plasma lipid parameters in dementia [17,18,[29][30][31]. Most of these studies compared the plasma lipid profiles of AD subjects with those of multiinfarct dementia and considered their value in differential diagnosis [17,18,29,31].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Serum-Lipid-Related Cardiovascular Risk Factors in Alzheimer’s Disease

Kálmán

Kudchodkar

Murray

et al. 1999

Dement Geriatr Cogn Disord

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“…Atherosclerosis and stroke, conditions that share hypercholesterolemia as a risk factor, appear to be associated with AD as well (23)(24)(25)(26). Indeed, epidemiological studies indicate that high serum cholesterol levels increase the risk of AD, and it has been proposed that the homeostatic regulation of cholesterol metabolism may be altered in AD (27). In contrast, recent reports show a significant reduction in AD risk for patients treated with statins, a group of cholesterol-lowering drugs (28,29).…”

mentioning

confidence: 77%

Statins Cause Intracellular Accumulation of Amyloid Precursor Protein, β-Secretase-cleaved Fragments, and Amyloid β-Peptide via an Isoprenoid-dependent Mechanism

Cole

Grudzien

Manhart

et al. 2005

Journal of Biological Chemistry

139

148

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The use of statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that block the synthesis of mevalonate (and downstream products such as cholesterol and nonsterol isoprenoids), as a therapy for Alzheimer disease is currently the subject of intense debate. It has been reported that statins reduce the risk of developing the disorder, and a link between cholesterol and Alzheimer disease pathophysiology has been proposed. Moreover, experimental studies focusing on the cholesterol-dependent effects of statins have demonstrated a close association between cellular cholesterol levels and amyloid production. However, evidence suggests that statins are pleiotropic, and the potential cholesterol-independent effects of statins on amyloid precursor protein (APP) metabolism and amyloid ␤-peptide (A␤) genesis are unknown. In this study, we developed a novel in vitro system that enabled the discrete analysis of cholesterol-dependent and -independent (i.e. isoprenoid-dependent) statin effects on APP cleavage and A␤ formation. Given the recent interest in the role that intracellular A␤ may play in Alzheimer disease, we analyzed statin effects on both secreted and cell-associated A␤. As reported previously, low cellular cholesterol levels favored the ␣-secretase pathway and decreased A␤ secretion presumably within the endocytic pathway. In contrast, low isoprenoid levels resulted in the accumulation of APP, amyloidogenic fragments, and A␤ likely within biosynthetic compartments. Importantly, low cholesterol and low isoprenoid levels appeared to have completely independent effects on APP metabolism and A␤ formation. Although the implications of these effects for Alzheimer disease pathophysiology have yet to be investigated, to our knowledge, these results provide the first evidence that isoprenylation is involved in determining levels of intracellular A␤.A growing body of evidence suggests that the amyloid ␤-peptide (A␤) 1 plays a critical and early role in Alzheimer disease (AD) pathogenesis. AD is characterized by cerebral amyloid plaques, which are extracellular deposits of A␤ (1, 2). Overproduction of the 42-amino acid form of A␤ (A␤42) is associated with early onset familial AD, and A␤42 appears toxic to neurons in vitro and in vivo (reviewed in Refs. 3 and 4). Moreover, recent reports suggest that, in addition to extracellular A␤, the accumulation of intracellular A␤ may be involved in AD (5-15). Thus, much research has been devoted to understanding the role of A␤ in AD and to developing therapeutic strategies for reducing A␤ levels or toxicity. A␤ is cleaved from amyloid precursor protein (APP) by two proteases, the ␤-and ␥-secretases (reviewed in Refs. 4, 16, and 17). Initially, ␤-secretase (also known as BACE1) cuts APP at the N terminus of the A␤ domain to produce the membranebound APP C-terminal fragment (CTF) C99 and the secreted APP ectodomain APPs␤. C99 is the substrate of ␥-secretase, which cleaves to generate the C terminus of A␤. ␥-Secretase cleavage is heterogeneous and produces A␤ peptides of different le...

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“…Moreover, longitudinal clinical studies suggest that stroke and AD occur in tandem more often than by chance alone (Kalaria, 2000;Aliev, 2002;Aliev et al, 2002c;de la Torre, 2002b). These studies suggest that vascular reshaping and lipid physiology are closely linked to AD, and this linkage is part of the pathophysiology of AD rather than a consequence (Knebl et al, 1994;Baggio et al, 1998;Koudinov et al, 1998;Aliev, 2002;Aliev et al, 2002a,b,c;de la Torre, 2002b). Unfortunately, the nature of this relationship remains virtually unexplored (Kalaria, 1999;Aliev, 2002;Aliev et al, 2002b,c;de la Torre, 2002b).…”

Section: The Pathogenetic Mechanisms Of Cerebrovascular Diseases and Admentioning

confidence: 88%

“…These factors contribute to the progressive cognitive decline characteristic of patients with AD, as well as regional functional and anatomical pathology, consisting of synaptic loss, senile plaque (SP) and neurofibrillary tangle (NFT) formation, tissue atrophy, and progressive neurodegeneration (de la Torre, 2000;2002a,b). The level of total serum, especially low density lipoproteins (LDL), and ApoB are associated with increased deposition of Aß in demented individuals with postmortem confirmed AD (Knebl et al, 1994;Baggio et al, 1998;Koudinov et al, 1998;Kuo et al, 1998). Moreover, comparisons between ventricular fluid (VF) lipoproteins isolated from AD patients and age-matched non-demented patients, show that cerebral spinal fluid (CSF) lipoprotein metabolism is altered in AD (Montine et al, 1997) and clearly supports our idea that there is a direct relationship between vascular and lipoprotein failure in AD.…”

Section: Vascular Abnormalities Are a Prominent Feature Of Admentioning

confidence: 99%

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

et al. 2003

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Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.

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Plasma lipids and cholesterol esterification in Alzheimer's disease

Cited by 32 publications

References 18 publications

Evaluation of Serum-Lipid-Related Cardiovascular Risk Factors in Alzheimer’s Disease

Evaluation of Serum-Lipid-Related Cardiovascular Risk Factors in Alzheimer’s Disease

Statins Cause Intracellular Accumulation of Amyloid Precursor Protein, β-Secretase-cleaved Fragments, and Amyloid β-Peptide via an Isoprenoid-dependent Mechanism

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Alzheimer disease

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