Biomedical Engineering Reference
In-Depth Information
In this regard, maladaptive neuronal plasticity may play a major role in AD. Several
studies have shown that Aβ binds to integrins and activates the focal adhesion
proteins paxillin and focal adhesion kinase, which are downstream of integrin
receptors, suggesting that focal adhesion signaling cascades might be involved
in Aβ-induced neuronal dystrophy and cell death. h erefore, characterization of
the molecular pathway(s) by which Aβ induces neuronal dystrophy may suggest
therapies to block maladaptive plasticity to preserve neuronal function and
synaptic integrity.
Recent studies report that integrins bind both the soluble and i brillar forms
of Aβ, mediating Aβ signal transmission from extracellular sites into the cell and
ultimately to the nucleus. h us, integrins probably play a role in AD pathology
as potential neuronal and glial receptors mediating Aβ-induced cytotoxicity. Aβ
can form a meshwork that resembles an extracellular matrix, and cells are known
to attach to both soluble and i brillar Aβ-coated plates in an integrin-dependent
manner. Evidence was provided by Wright
et al
. (2007) that integrins mediate
attachment of Aβ to the cell surface: Aβ deposition on the cell surface was inhibited
by specii c adhesion-blocking antibodies for αv and β1 integrins. Integrins
containing the αv subunit are widespread throughout the brain, including the
hippocampus. h e i nding that the αv integrin-specii c antibody was an ef ective
antagonist of Aβ both
in vivo
and
in vitro
indicates that the prevention of LTP
inhibition
in vivo
is due to a direct action in the hippocampus. Such evidence
supports the potential therapeutic usefulness of antibodies to target αv integrins
within the brain or small molecule antagonists of αv integrins. h e compound
SM256, when injected systemically, prevented the inhibition of LTP by centrally
applied Aβ (Wang
et al
. 2008). h is proof of concept provides encouragement for
the search for potent and selective integrin subtype antagonists.
Fibrillar Aβ has been shown to induce apoptotic cascades in neurites and
synapses. h us, aberrant focal adhesion activation by Aβ may lead to the initiation
of localized apoptotic cascades normally involved in adaptive plasticity in both
neurites and synapses. Brain regions with the highest plasticity are most vulnerable
in AD, suggesting that under pathological conditions such as presenilin mutations
or Aβ deposition, neuronal plasticity may result in neuronal dysfunction.
Integrins can also interact with other membrane-bound proteins, including
CD147, which is a transmembrane glycoprotein and a member of the
immunoglobulin superfamily (IgSF) of receptors that associate with two integrin
isoforms, α3β1 and α6β1, at points of cell-cell contact. CD147 has been observed
to be a component of the γ secretase complex, which is an important regulator of
the production of Aβ peptides. Results from experimental models have shown that
the deletion of cellular CD147 from the γ secretase complex by RNA interference
results in an increase in Aβ peptide production.
Interestingly, neurological abnormalities observed in CD147-null mice,
including spatial learning and memory dei cits, are similar to those observed in
