Biology Reference
In-Depth Information
by significantly greater epithelial-cell atrophy, with cell height decreasing up to
22% relative to age-matched controls
[20]
. Moreover, AD leads to a greater intra-
cellular distribution of lipofuscin vacuoles and Biondi Ring tangles in the CP
[21]
.
Concomitant to late-onset AD, the CP epithelial basement membrane becomes very
irregular and thickens an additional 28% beyond that seen in age-matched controls
[20]
. Additional pathological features reminiscent of AD pathology that occur in CP
include fibrotic stroma of the villi, with extensive vascular thickening and numerous
hyaline bodies, and calcifications with deposits of IgG, IgM, and C1q along the epi-
thelial basement membrane
[21,27]
. These structural confounds lead to reduced CSF
secretion, reducing turnover to 36 hours in AD patients
[22]
.
The progression of atrophy in choroidal epithelial cells in AD is associated with
pronounced reductions in secretory activity and transport functions. Levels of tran-
sthyretin (TTR), a CP-synthesized molecule that associates with -amyloid peptide
to form complexes, are more than 10% lower in AD
[30]
. Levels of ascorbic acid and
-tocopherol, the two major scavengers of free radicals in CSF, are decreased in AD,
likely adding to oxidative stress
[31,32]
. CSF folate and vitamin B12 (important for
methylation of numerous molecules) are significantly lower
[33-35]
, while homo-
cysteine, which mediates lipid peroxidation and increases the production of toxic
(
E
)-4-hydroxy-2-nonenal, is increased in AD CSF. The impaired ability of the CP to
clear molecules from the CSF has profound implications
[22]
. In rats, clearance of
intraventricularly injected -amyloid peptide decreases from 10.4 l/min at 3 months
of age to 0.71 l/min at 30 months. Consequently, in young rats the brain content
of amyloid peptide increases from 7% at the end of CSF perfusion as compared to
49% in old animals
[29]
. The increase of 1-40 and 1-42 amyloid peptide levels in
elderly humans could be related to decreased clearance from the CNS.
Decreased CSF production could also enhance protein glycation and the format-
ion of -amyloid oligomers
[22]
. The AD brain contains elevated levels of glyca-
tion products and deposits of amyloid peptide; senile plaques and fibrillary tangles
contain advanced glycation products
[22]
. Glycation promotes protein aggregation,
the polymerization of tau microtubule associated proteins, and protein -amyloid
peptide aggregation. The reduced CSF turnover, the increase of protein glycation,
and the diminution of -amyloid clearance, taken together, could induce oligomer
formation and retention. More importantly, the compromised ability of the CP to
perform its CNS homeostasis functions could exacerbate AD progression, leading to
methylation problems, increased oxidative stress and lipid peroxidation, decreased
amyloid clearance, augmented tau protein polymerization, and formation of amyloid
peptide oligomers and fibrils
[22]
.
4.7 Choroid Plexus as Transplantable Cells
for Brain Repair: Pilot Studies
Cell therapy has emerged as an experimental treatment for CNS disorders. The
observation that CP function deteriorates as a result of aging and pathologic condi-
tion provides the impetus to rescue the damaged CP by transplanting healthy CP
[9]
.
