The Mysterious Link between Cholesterol and Alzheimer's Disease: Is the Blood-Brain Barrier a Suspect?
Fabien Gosselet1, 2, 3*
1Lille Nord de France University, F-59000 Lille, France
2LBHE, University of Artois, F-62300 Lens, France
3IMPRT-IFR114, F-59000 Lille, France
- Corresponding Author:
- Dr. Fabien GOSSELET
Université Lille Nord de France/d’Artois
Laboratoire de Physiopathologie de la Barrière Hémato-encéphalique, EA 2465 - IMPRT 114
Faculté Jean Perrin, Rue Jean Souvraz
S.P. 18, F-62300 Lens, France
Tel: + 33 321 791 780
Fax: +33 321 791 736
E-mail: [email protected]
Received date: June 27, 2011; Accepted date: July 20, 2011; Published date: July 22, 2011
Citation: Gosselet F (2011) The Mysterious Link between Cholesterol and Alzheimer's Disease: Is the Blood-Brain Barrier a Suspect? J Alzheimers Dis 1:103e. doi:10.4172/2161-0460.1000103e
Copyright: © 2011 Gosselet F. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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It is now well accepted that the deposition and aggregation of
) peptides are hallmarks of Alzheimer's disease (AD)
. These peptides are constitutively secreted by neurons but (for
reasons that remain to be established) Aβ
metabolism is altered in
AD patients and leads slowly to the neurodegenerative process. With
these considerations in mind, the identification of genetic, biochemical,
environmental and dietary factors influencing Aβ
clearance and degradation became a high priority for researchers
working on AD. The enzyme responsible for Aβ
peptide synthesis was
soon identified as a β
-secretase called β
-site amyloid precursor protein
cleaving enzyme 1 (BACE1) . The most important genetic risk factor
for late-onset AD was identified as the APOe4 allele . This gene
encodes an apolipoprotein, a protein component of the low-density
lipoprotein (LDL) particles involved in lipid transport throughout the
body; this finding highlighted a probable relationship between AD
and cholesterol metabolism. More recently, two other susceptibility
loci linked to cholesterol metabolism have been identified in AD:
CLU (coding for clusterin, another apolipoprotein)  and ABCA7
 (coding for the ATP-binding cassette sub-family A member 7
transporter involved in cholesterol homeostasis  ). This link between
AD and cholesterol metabolism was reinforced by the observation
that the sterol can modulate BACE1 activity and promote Aβ
biosynthesis . Cholesterol was also identified as dietary risk factor in
humans; since elevated serum cholesterol is a risk factor for developing
AD and amount of Aβ
peptide in the brain correlates with serum
levels of LDL and total cholesterol [8,9]. Moreover, rabbits and mice
on a cholesterol-enriched diet show elevated serum cholesterol levels,
peptide deposition and cognitive impairment [10-14].
However, the reasons why serum cholesterol influences AD are difficult
to determine, for two main reasons. Firstly, most of the accretion of
cholesterol in the central nervous system (CNS) is due to de novo
synthesis (reviewed in ). Secondly, the brain is isolated from the rest
of body by the blood-brain barrier (BBB), a dynamic interface formed
by brain capillary endothelial cells (BCECs) and sealed by complex
tight junctions that restrict the paracellular pathway . One of the
BBB's main roles is to supply the brain with essential nutrients and
mediate the efflux of many waste products. To this end, BCECs express
specific receptors or transporters in their luminal (plasma-side) and/
or abluminal (brain-side) membranes that force molecules to take the
At present, it is not fully accepted that peripheral cholesterol
can cross the BBB and thus influence brain cholesterol homeostasis.
Given the lack of in vitro BBB models, initial animal studies have
consisted in injecting radioactive sterols and thus estimating the
ability of lipoproteins to reach the CNS. No significant blood-to-brain
fluxes of radiolabelled LDL-, high-density lipoprotein- (HDL-) or
free cholesterol were detected in guinea pigs, rabbits, sheep and mice
[17,18]. In baboons fed with radioactive sterol and in humans injected
with labeled cholesterol, there was a very slight signal in the brain,
which was considered to be negligible because it corresponded to a
very low fraction of serum cholesterol [19,20]. With the development of new techniques, some recent studies have found that an increase in
serum cholesterol levels alters Aβ
peptide metabolism - even when
there an increase in brain cholesterol content was absent [11,21,22] or
slight [12,23,24]. These discrepancies have contributed to the notion
that the BBB prevents peripheral cholesterol entry into the brain.
However, clinical observations strongly suggest that this exchange
between brain and plasma compartments does occur. For example, the
cholesterol derivative cholestanol is abnormally produced by the liver
in patients with cerebrotendinous xanthomatosis caused by a genetic
deregulation in bile acid synthesis . The cholestanol crosses the
BBB and accumulates in the brain. Moreover, with the development
of capillary extraction methods and in vitro BBB models over the last
two decades, other researchers have focused on the BCECs' ability
to transfer cholesterol from the blood to the brain. We and others
have demonstrated that BCECs express important receptors and
transporters involved in lipoprotein uptake and transcytosis; such as
the ATP-binding cassette sub-family A and G members 1 (ABCA1 and
ABCG1), ABCA7, scavenger receptor class B member 1 (SCARB1) and
the low-density lipoprotein receptor (LDLR) [26-32]. These receptors
and transporters promote the movement of LDL and cholesterol
across BCECs (our unpublished data and [26,29,31,33]) and the
BBB . Moreover, this transport appears to be regulated by glial
cells, which can modulate expression of LDLR, ABCA1 and ABCG1
[28,30]. These findings suggest that glial cells communicate with
BCECs to compensate for deficiencies or changes in brain cholesterol
metabolism. Although ApoE is the major apolipoprotein in the CNS,
some studies have revealed the presence of other apolipoproteins (such
as ApoA-I). Given that cells from the CNS are unable to synthesize this
apolipoprotein, it was suggested that ApoA-I may be imported from
the blood into the brain across the BBB by an HDL-mediated process
[33,35]. Lastly, one of the strategies developed to deliver molecules to
the CNS as a whole involves fusion with apolipoproteins. This approach
has proven to be very effective and confirms that a receptor-mediated
process lipoprotein deliver occurs at the BCECs' apical face [36-38]. In conclusion, it is now clear that a very small fraction of serum
lipoproteins may enter the brain across the BBB. On the timescale of
hours or days, this fraction may be negligible. However, over several
decades, this small fraction may influence the brain's cholesterol metabolism and thus the development of neurological diseases like
AD. The molecular mechanisms involved in this process remain
poorly characterized and need further investigation. Furthermore,
in addition to lipoproteins, cholesterol may efficiently cross the BBB
after undergoing specific hydroxylation at the 27 and 24 positions by
27-hydroxylase enzyme and 24-hydroxylase (the latter being located
exclusively in CNS), respectively [39,40]. These metabolites are called
"oxysterols" and are natural ligands for the liver X nuclear receptors
that regulate the expression of specific genes controlling cholesterol
homeostasis, such as ABCA1 or ABCG1. Oxysterols also seem capable
of modulating Aβ
peptide synthesis [39,40] but their effects at the BBB
level are poorly characterized - demonstrating once again that the
barrier's role in brain cholesterol homeostasis (and thus in AD) has
probably been underestimated.
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