Elevated plasma cholesterol does not affect brain Aβ in mice lacking the low‐density lipoprotein receptor

Abstract

Epidemiological studies support an association between vascular risk factors, including hypercholesterolemia, and Alzheimer's disease (AD). Recently, there has been much interest in the possibility that hypercholesterolemia might directly promote b-amyloid (Ab) production. Indeed, in vitro studies have shown that increasing cellular cholesterol levels enhances Ab production. However, studies in AD transgenic mouse models have not consistently found that elevated plasma cholesterol leads to increased Ab production or deposition in vivo. In this study, we determined whether elevated peripheral cholesterol influences Ab production in mice with a null mutation of the low-density lipoprotein receptor (LDLR). We show that dramatically elevated plasma cholesterol levels, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, did not affect either levels of brain Ab40, Ab42, or APP, or the Ab42/40 or APP-CTF/APP ratios, nor substantially alter brain cholesterol levels. ApoE protein levels in brain were, however, elevated, in LDLR)/) mice by post-transcriptional mechanisms. Collectively, these studies argue that plasma cholesterol levels do not normally regulate production of brain Ab.

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

“…Indeed while longer term exposure to elevated serum cholesterol may eventually impact behavior, the 16-week exposure studied here seems to have had few if any behavioral effects. This lack of effect is, however, consistent with our recent findings that dramatically elevated plasma cholesterol levels in LDLR-/-mice, whether induced by high cholesterol, high fat, or high fat/high cholesterol diets, do not substantially alter brain cholesterol levels nor affect levels of brain Aβ 40 or 42 [11].…”

“…LDLR itself is expressed in the brain, and while it has generally been considered to be less important functionally in the nervous system [13] than other LDLR family members, several recent studies have suggested that LDLR may affect brain function [11,12,19,23]. We therefore undertook a detailed behavioral analysis of LDLR-/-mice and in addition given the interest in serum cholesterol as a possible risk factor for the cognitive dysfunction seen in AD [3,5,28], we used the fact that serum cholesterol levels can be modulated by diet in LDLR-/-mice [31] to examine the effects of systemic hypercholesterolemia on behavioral function as well.…”

“…Yet LDLR-/-mice have been reported to exhibit defects in spatial memory [23]. In addition, LDLR is upregulated in brain following ischemic injury [19], and brain ApoE levels are elevated in LDLR-/-mice [11,12], suggesting that LDLR may be an important ApoE receptor in brain.…”

Low-density Lipoprotein Receptor Represents an Apolipoprotein E-independent Pathway of Aβ Uptake and Degradation by Astrocytes

“…However, in PDAPP mice crossed to LDLR Ϫ/Ϫ mice there was no significant change in human A␤ levels, although there was a trend toward increased A␤ deposition in mice lacking LDLR (36). A different group looking at the effect of LDLR deletion on mouse A␤ levels found no changes in comparison to WT mice (49). Our studies have found that LDLR overexpression in the mouse brain dramatically decreased A␤ deposition in APP/PS1 transgenic mice.…”

“…In mouse studies, modulation of LDLR protein levels in the brain altered apoE amounts. LDLR Ϫ/Ϫ mice had significantly elevated amounts of apoE in the brain and cerebrospinal fluid (36,37,49,50), whereas mice overexpressing LDLR in the brain had lower levels of apoE (27). In the current study, we demonstrate that modulation of LDLR levels in astrocytes similarly alters apoE levels.…”