Adhesion Molecules in Dementia - Adhesion Molecules - page 481

hippocampal neurons, the puncta adherentia junctions, which are thought to
be mechanical anchoring sites that stabilize neurotransmitter release sites and
which also contain homophilic cadherin complexes. Interestingly, the disruption
of nectin interactions at the developing synapse in vitro was found to result in a
signii cant decrease in synapse size followed by a possibly compensatory increase
in the overall number of synapses (Mizoguchi et al . 2002).
Circulating adhesion molecules have been found in the sera of healthy
individuals, and increased levels have been described in dementia-related neuro-
degeneration and aging. h ese observations point to an abnormal processing and/
or shedding of IgCAMs, which may rel ect changes in adhesion molecule-related
cell interactions. h ere is also some evidence that circulating adhesion molecules
interfere with various cell-cell interactions and may act as signal transducers, but
their full biological roles remain unclear.
Concentrations of soluble L1 and NCAM were found to be signii cantly
increased in the cerebrospinal l uid (CSF) of AD patients compared to a normal
control group. Proteolytic fragments of L1, but not NCAM, were also elevated
in patients with vascular dementia and dementia of mixed type (Strekalova
et al . 2006). Elevated levels of soluble forms of intercellular adhesion molecule 1
(sICAM-1, or CD54), vascular cellular adhesion molecule 1 (VCAM-1, or CD106),
and the CD40 ligand (CD40L, or CD154) have been reported in patients with
various brain diseases, such as atherosclerosis, ischemic stroke, cerebrovascular
disease and AD (Fassbender 1999, Rentzos 2004).
ICAM-1 can be upregulated by several cytokines such as interferon-γ,
interleukin-1 and tumor necrosis factor α, and in central nervous system (CNS)
pathologies ICAM-1 is aberrantly expressed by cerebral endothelial cells and
astrocytes. In vitro , the Alzheimer`s peptides (Aβ) have also been shown to induce
expression of ICAM-1 in cultured vascular endothelial cells and to induce leukocyte
adherence and endothelial and smooth muscle cell activation. Experimental
studies also show that Aβ-induced microglia activation and tau phosphorylation
are dependent on CD40/CD40L interaction, and that the inhibition of CD40L
results in decreased amyloid production and microglia activation in a transgenic
animal model of AD (Tan et al . 1999). h us, higher levels of sICAM-1 and sCD40
in AD patients correlate with Aβ pathology. h is is further supported by post-
mortem studies of AD patients that revealed upregulated CD40 in blood vessel
walls (Togo et al . 2000) and localization of ICAM-1 in senile plaques (Akiyama
et al . 1993).
While ICAM-1 is expressed on a broad variety of cells, the expression of
VCAM-1, another member of the immunoglobulin superfamily, is more restricted
to endothelial cells, and VCAM-1 is assumed to be involved in lymphocyte,
monocyte, and eosinophil but not neutrophil adhesion to activated endothelium.
At er i rm adhesion, leukocytes proceed to transendothelial migration through
adhesion mediated by platelet-endothelial cell adhesion molecule 1 (PECAM-1),