Biomedical Engineering Reference
In-Depth Information
was associated with poor cognitive performance and greater risk of cognitive
decline over the follow-up period. Similar associations between elevated baseline
C-reactive protein levels and greater cognitive decline have been reported in
patients followed for 5 to 6 yr (Tilvis
et al
. 2004).
h e trai cking of lymphocytes among blood and lymphoid and non-lymphoid
tissue depends on the expression of specii c adhesion molecules, including the
membrane glycoprotein L-selectin (CD62L). L-selectin is constitutively expressed
on all classes of leukocytes, including naïve T lymphocytes, which utilize L-selectin
to migrate through lymph nodes and other secondary lymphoid tissue. L-selectin
mediates leukocyte rolling on vascular endothelium at sites of inl ammation and
lymphocyte migration to peripheral lymph nodes. L-selectin is rapidly shed from
the cell surface at er leukocyte activation by a proteolytic mechanism that cleaves
the receptor in an extracellular region proximal to the membrane. h is process
may allow rapid leukocyte detachment from the endothelial surface before entry
into tissues.
h e transition from a naïve to an activated memory T cell is generally
accompanied by a shedding of L-selectin. CD8+ memory T cells, for example,
acquire a distinct proi le of other adhesion molecules that permits them to
preferentially migrate through the tissue in which they were activated. A dei ciency
in L-selectin has been associated with alterations in both lymphocyte migration
and reduced immune responsiveness (Steeber
et al
. 1996). Patients with AD who
were classii ed as vulnerable showed reduced levels of circulating CD4
+
and CD8
+
and CD62L
-
T lymphocytes, possibly as a result of increased sympathomedullary
activation (Mills
et al
. 1999). In general, these i ndings seem consistent with
previous studies demonstrating functional immune dei cits in elderly patients
with AD and suggest the identity of specii c lymphocyte subsets related to this
phenomenon.
Internalized amyloid precursor protein either recycles to the plasma membrane,
where α-secretase resides, or moves to acidic compartment(s) for β-secretase
exposure. While the trans-Golgi network contains β-secretase activity, recent
examination of the subcellular distribution of this protease, called β-amyloid
cleaving enzyme, has led to the suggestion that β-secretase activity might also
reside at the plasma membrane and in endosomes. To examine the role of endocytic
compartments in β-secretase processing of amyloid precursor protein, the wild-
type and endosomal sorting mutant P-selectin cytoplasmic domains were used
to control movement of amyloid precursor protein through endosomes. Amyloid
precursor protein/P-selectin, which is sorted from early to late endosomes,
undergoes signii cantly less α-secretase cleavage, and more β-secretase cleavage,
than amyloid precursor protein/P-selectin768A, a mutant that recycles more
ei ciently to the cell surface. h ese results demonstrate that endosomal sorting
inl uences the relative exposure of the amyloid precursor protein/P-selectin
chimeras to α- and β-secretase activities and suggest that, because delivery to
