LDL receptor deficiency results in decreased cell proliferation and presynaptic

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Neurosci Res. 2007 Nov;59(3):251-6. Epub 2007 Jul 17.
Mulder M, Koopmans G, Wassink G, Al Mansouri G, Simard ML, Havekes LM,
Prickaerts J, Blokland A.
Department of Molecular Cell Biology, University of Maastricht, Maastricht, The
Netherlands.


An aberrant cholesterol metabolism in the brain may contribute to the
pathogenesis of Alzheimer's disease (AD). The LDL receptor (LDLR) regulates
plasma cholesterol levels and recently we and others obtained evidence that it
is also involved in regulating brain cholesterol homeostasis. Moreover, we found
that LDLR-deficient mice display impaired spatial memory. Because cholesterol,
in part derived from cellular uptake via LDLR, is required for peripheral cell
proliferation and growth, we examined the effect of absence of the LDLR on
hippocampal proliferation and the density of synaptic connections. Mice
deficient for the LDLR displayed a reduced number of proliferating
(BrdU-labeled) cells in the hippocampus as compared to wild type control mice.
In addition, the number of synaptophysin-immunoreactive presynaptic boutons in
the hippocampal CA1 and the dentate gyrus (DG) areas, but not in cortical areas,
was lower in the LDLR-knockout mice than in the control mice. In vitro
experiments showed that LDLR activity is increased when cell growth is enhanced
by the addition of N2 supplement. This further supports a role for the LDLR in
the outgrowth of neurites. These findings support the notion that, similar to
its role in the periphery, the LDLR is important for the cellular uptake of
cholesterol in the brain and that disturbance of this process affects neuronal
plasticity.

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