Biomedical Engineering Reference
In-Depth Information
mouse models of AD. Although the mechanism by which CD147 attenuates the
production of amyloid β peptides is unknown, further studies of CD147 function
within the γ secretase complex may promote the development of new AD therapy.
α6β1 integrins associated with CD147 bind amyloid β peptides and initiate a signal
transduction cascade in microglial cells (Bamberger
et al
. 2003), indicating the
potential for another level of regulation inl uenced by CD147 expression in AD.
h us, a pathological relationship among Aβ deposition, neuronal dystrophy, and
synaptic loss may lead to cognitive impairment in AD. h e molecular mechanism
by which neuronal dystrophy occurs is unclear. Neuronal dystrophy and cell death
induced by i brillar Aβ take place over dif erent time intervals and at dif erent Aβ
concentrations, pointing to the possibility that the two events are mediated by
two distinct molecular mechanisms. Extracellular signals producing alterations in
the cytoskeleton are ot en transduced through adhesion proteins. In this regard,
Aβ could promote dystrophy by aberrantly activating signal transduction cascades
leading to cytoskeletal changes.
THE CADHERIN SUPERFAMILY MEMBERS IN DEMENTIA
Cadherins constitute a superfamily comprising more than 100 members in
vertebrates, grouped into subfamilies that are designated as classic cadherins,
desmosomal cadherins, protocadherins, Flamingo/CELSRs and focal adhesion
targeting domain. With a few exceptions, cadherins are transmembrane proteins. In
cadherin-based adherens junctions, the extracellular domains of transmembrane
cadherins promote cell-cell adhesion by engaging in Ca
2+
-dependent homophilic
interactions, while the cytoplasmic domains are linked to the actin cytoskeleton
via α- and β-catenins. Classical cadherins, including epithelial (E)- and neural
(N)-cadherins, are major cell-cell adhesion receptors involved in axon sorting
and in the regulation of physiological functions of the brain, such as long-term
potentiation in the hippocampus. Both E- and N-cadherins have been found at the
synapse and are reported to play key roles in synaptic structure and function.
Recent i ndings point out the important relationship between cadherins and
presenilin-1 (PS1) in the brain. PS1 has been the subject of intensive study in
relation to AD, since it has been shown that PS1 mutations are linked to familial
Alzheimer's disease (FAD). PS1 is a member of the high molecular weight complex
of γ-secretase, which generates the carboxyl end of β-amyloid peptide (gamma-
cleavage) and leads to the accumulation of the Aβ peptide in amyloid plaques
in AD-af ected brains. Recent evidence suggests that upon formation of cell-cell
contacts, presenilin colocalizes with cadherins and stabilizes the cadherin-based
adhesion complex. PS1 forms complexes with E-cadherin and N-cadherin and
it has been localized at synaptic sites. h us, PS1 is suggested to have two distinct
activities: (1) Under conditions promoting cell-cell adhesion, incorporation of
PS1 into the E-cadherin-catenin complex may result in the stabilization of cell-cell
