Elevated Serum Total and LDL Cholesterol in Very Old Patients with Alzheimer’s Disease

Lesser, Gerson T.; Kandiah, Kesavan; Libow, Leslie S.; Likourezos, A; Breuer, Brenda; Marin, Deborah B.; Mohs, Richard C.; Haroutunian, Vahram; Neufeld, Richard R.

doi:10.1159/000051248

Cited by 72 publications

(53 citation statements)

References 56 publications

(92 reference statements)

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“…Primary Neuronal Cultures-Primary neuronal cultures were generated from dissociated cortices and hippocampi of 17-19-day-old Sprague-Dawley rat embryos, and neurons were plated at a density of 1 ϫ 10 5 /ml in 24-well plates on cover slides as described previously (34). Neurons were treated with fibrillar A␤ 42 with or without human apoA-I at in vitro day 5.…”

Section: Cell Culture Cytotoxicity and Apoptosis Assaysmentioning

confidence: 99%

Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice

Lefterov

Fitz

Cronican

et al. 2010

Journal of Biological Chemistry

112

110

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A hallmark of Alzheimer disease (AD) is the deposition of amyloid ␤ (A␤) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases A␤ 40 aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of A␤ 42 and decreases A␤ 42 toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1⌬E9 to apoA-I KO mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1⌬E9 mice. Further characterization of APP/PS1⌬E9/apoA-I KO mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble A␤ oligomer levels, A␤ plaque load, or levels of insoluble A␤ in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble A␤ isolated from cerebral blood vessels. Our data show that in APP/PS1⌬E9/apoA-I KO mice, insoluble A␤ 40 is increased more than 10-fold, and A␤ 42 is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1⌬E9/apoA-I KO mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased A␤ toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1⌬E9 mice in parallel to significantly increased cerebral amyloid angiopathy.

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Section: Cell Culture Cytotoxicity and Apoptosis Assaysmentioning

confidence: 99%

Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice

Lefterov

Fitz

Cronican

et al. 2010

Journal of Biological Chemistry

112

110

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“…Interestingly, hypercholesterolemia itself has been suggested to be an independent risk factor for brain disease. In particular, elevated serum cholesterol has been suggested to increase the risk of developing Alzheimer's disease (AD) [3,5,21,28]. Why hypercholesterolemia might promote AD is not understood.…”

Section: Introductionmentioning

confidence: 99%

Increased locomotor activity in mice lacking the low-density lipoprotein receptor

Elder

Ragnauth

Dorr

et al. 2008

Behavioural Brain Research

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While the low-density lipoprotein receptor (LDLR) is best known for its role in regulating serum cholesterol, LDLR is expressed in brain, suggesting that it may play a role in CNS function as well. Here, using mice with a null mutation in LDLR (LDLR-/-), we investigated whether the absence of LDLR affects a series of behavioral functions. We also utilized the fact that plasma cholesterol levels can be regulated in LDLR-/-mice by manipulating dietary cholesterol to investigate whether elevated plasma cholesterol might independently affect behavioral performance. LDLR-/-mice showed no major deficits in general sensory or motor function. However, LDLR-/-mice exhibited increased locomotor activity in an open field test without evidence of altered anxiety in either an open field or a light/dark emergence test. By contrast, modulating dietary cholesterol produced only isolated effects. While both C57BL/6J and LDLR-/-mice fed a high cholesterol diet showed increased anxiety in a light/dark task, and LDLR-/-mice fed a high cholesterol diet exhibited longer target latencies in the probe trial of the Morris water maze, no other findings supported a general effect of cholesterol on anxiety or spatial memory.

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“…Reduced high-density lipoprotein cholesterol (HDL-C) (3)(4)(5)(6)(7)(8)(9) and apolipoprotein A-1 levels (3), as well as increased levels of lipoprotein (a) (5) have been observed in dementia in some but not all studies. There also have been contradictory results in studies relating total cholesterol (10,11) and low-density lipoprotein cholesterol (LDL-C) (6,8,11) to dementia.…”

Section: Introductionmentioning

confidence: 99%

Impact of plasma lipids and time on memory performance in healthy elderly without dementia

Reitz¹,

Luchsinger²,

Tang³

et al. 2005

Neurology

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Objective-To examine the association of plasma lipid levels to changes in cognitive function in the elderly without dementia.Methods-We examined changes in performance in tests of memory, visuospatial/cognitive and language abilities in 1147 elderly individuals without dementia or cognitive impairment at baseline followed for seven years using generalized estimating equations.Results-Performance in all cognitive domains declined significantly over time, while there was no association between levels of any plasma lipid or lipid lowering treatment and memory, cognitive/ visuospatial or language performance at any interval. Higher age at baseline was related to lower scores in all three domains at each interval, while higher education and Caucasian ethnicity were associated with higher scores in all domains. Analyses relating plasma lipids to performance in color trails tests using proportional hazards regression showed no association.In subsequent analyses excluding subjects with incident dementia, memory performance declined over time, while cognitive/visuospatial and language performance did not. Higher plasma HDL and total cholesterol were associated with higher scores in language performance at baseline; this domain declined faster among individuals with higher total cholesterol, but this result was not significant after taking multiple comparisons into account. Plasma triglycerides, LDL, or treatment with lipid lowering agents were not associated to changes in cognitive performance.Conclusions-Plasma lipid levels or treatment with lipid lowering agents in the elderly were not associated with changes in cognitive function.

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Elevated Serum Total and LDL Cholesterol in Very Old Patients with Alzheimer’s Disease

Cited by 72 publications

References 56 publications

Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice

Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1ΔE9 Mice

Increased locomotor activity in mice lacking the low-density lipoprotein receptor

Impact of plasma lipids and time on memory performance in healthy elderly without dementia

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