Volume 5, Number
4, August 2003
Pages 267-269
Gillett MJ, Martins RN, Clarnette RC, Chubb P, Bruce DG, Yeap BB
Relationship between testosterone, sex hormone binding
globulin and plasma amyloid beta peptide 40 in older men with
subjective memory loss or dementia.
Abstract: In a group of 28 older men with either subjective memory
loss or dementia, serum total testosterone and sex hormone binding
globulin (SHBG) correlated inversely with plasma levels of amyloid
beta peptide 40 (Aß40, r=-0.5, P=0.01 and r=-0.4, P=0.04,
respectively). Calculated free testosterone was also inversely
correlated (r=-0.4, P=0.03), and all three relationships remained
statistically significant after allowing for age. A similar but
non-significant trend was seen with dehydroepiandrosterone sulphate
(DHEAS), and neither luteinising hormone (LH) nor estradiol
correlated with Aß40. These data demonstrate that lower androgen
levels are associated with increased plasma Aß40 in older men with
memory loss or dementia, suggesting that subclinical androgen
deficiency enhances the expression of Alzheimer’s disease-related
peptides in vivo. An inverse correlation exists between
SHBG and Aß40, warranting further investigation.
Commentary on the Gillett et al.
manuscript:
Pages 271-273
Suzana S. Petanceska
Age-associated androgen deficiency and Alzheimer's
disease: A case in the making?
Pages 275-286
Johannes A. Rhodin, Thom T. Thomas, Linda Clark, Amanda Garces,
Margaret Bryant
In vivo cerebrovascular actions of amyloid
ß-peptides and the protective effect of conjugated estrogens
Abstract: Vascular dysfunction and inflammatory processes may be
early events in the pathology of Alzheimer's disease (AD). Even
though amyloid ß-peptides (Aß) play a prominent role in the
initiation and progression of cellular dysfunction in AD, the
precise in vivo actions of various Aß-peptides has not been
established. The cerebrovascular actions of the major Aß-peptides
(1-40) and (1-42) in live animals were investigated using an open
cranial window technique. We show here that the Aß-peptides cause
vascular lesions, especially in the arterioles. In one set of
experiments, leukocytes and platelets were tagged with Rhodamine 6G,
soluble Aß(1-40) infused intravenously for 2 minutes, and the
vasculature video recorded for 90 minutes. In a second set of
experiments, soluble Aß(1-40) infusion was followed 30 minutes later
by an infusion of soluble Aß(1-42) and the vasculature recorded for
90 minutes. Fluorescent and transmission electron microscopic
examinations demonstrated the following cerebrovascular action of Aß-peptides:
endothelial cell damage, leukocyte adhesion, platelet activation,
thrombus formation, impeded blood flow, and smooth muscle cell
damage. The vascular disruption observed were similar to those
observed in the brains of some AD patients and may represent the
initial phase of a vascular inflammatory response associated with
cerebral amyloid angiopathy. The combination of Aß (1-40) and (1-42)
produced significantly more vascular disruption than Aß(1-40) alone.
Oral administration of conjugated estrogens in ovariectomized female
rats protected them from the deleterious actions of Aß-peptides. The
reported protective effect of estrogen against AD may be mediated in
part through prevention of cerebrovascular Aß action.
Pages 287-300
Julie Vining Smith and Yuan Luo
Elevation of oxidative free radicals in Alzheimer’s disease models
can be attenuated by Ginkgo biloba extract EGb 761
Abstract: The role of amyloid ß-peptide (Aß) in the free-radical
oxidative-stress model of neurotoxicity in Alzheimer’s disease (AD)
has received much attention recently. In this study, we have
employed both in vitro and in vivo models
displaying endogenous Aß production to study the effects of Aß on
intracellular free radical levels. We employed a neuroblastoma cell
line stably expressing an AD-associated double mutation, which
exhibits both increased secretion and intracellular accumulation of
Aß when stimulated, as well as transgenic Caenorhabditis elegans
constitutively expressing human Aß. A rise in levels of hydrogen
peroxide (H2O2) was observed in both in vitro and in
vivo AD-associated transgenic models expressing the Aß peptide
compared with the wild type controls. Treatment of the cells or C.
elegans with Ginkgo biloba extract EGb 761 significantly attenuated
the basal as well as the induced levels of H2O2-related reactive
oxygen species (ROS). Among individual EGb 761 components tested,
kaempferol and quercetin provided maximum attenuation in both
models. Furthermore, an age-dependent increase in H2O2-related ROS
was observed in wild type C. elegans, which is accelerated in the
AD-associated C. elegans mutant. These results support the
hypothesis of the involvement of Aß and ROS in association with AD.
Pages 301-308
Mar Pérez, Félix Hernández, Filip Lim, Javier Díaz-Nido and Jesús
Avila
Chronic lithium treatment decreases mutant tau protein
aggregation in a transgenic mouse model
Abstract: Tau protein hyperphosphorylation and aggregation
into neurofibrillary tangles are characteristic features of several
neurodegenerative disorders referred to as tauopathies. Among them,
frontotemporal dementia and Parkinsonism linked to chromosome 17 may
be caused by dominant missense mutations in the tau gene. Transgenic
mice expressing mutant tau serve as valid model systems to study the
ethiopathogenesis of these diseases and assay possible therapeutic
interventions. Here we report that chronic lithium treatment of a
transgenic mouse strain expressing human tau with three missense
mutations results in decreased glycogen synthase
kinase-3-dependent-tau phosphorylation and a reduction of
filamentous aggregates. These data indicate that lithium, presumably
acting through the inhibition of glycogen synthase kinase 3, may be
useful to curb neurodegeneration in tauopathies.
Pages 309-313
Joseph Quinn, Jung Suh, M. Milar Moore, Jeffrey Kaye, Balz Frei
Antioxidants in Alzheimer’s disease-Vitamin C delivery to a
demanding brain
Abstract: Levels of several antioxidants and related
markers were measured in cerebrospinal fluid (CSF) and plasma of 10
Alzheimer’s disease (AD) patients and 10 controls. Daily dosage of
vitamin C was significantly correlated with both plasma ((R=0.662;
p=0.0015) and CSF level (R=0.639, p=0.0024). Plasma and CSF vitamin
C levels were also highly correlated (R=0.793, p<0.0001). Similarly,
daily dosage of Vitamin E was significantly correlated with plasma
vitamin E (R=0.681; p=0.0009) and showed a trend toward correlation
with CSF vitamin E (R=0.422, p=0.06). There were no significant
differences between groups in absolute CSF or plasma levels of any
analyte. However, the CSF:plasma ratio of vitamin C was
significantly greater in the AD patients compared to the controls
(p=0.048). In a subset of AD patients, hippocampal volume was
significantly correlated with plasma (R2=0.833; p=0.004) and CSF (R2
=0.603; p=0.04) vitamin C levels, and inversely correlated with
CSF:plasma vitamin C ratio (R2 =0.717; p=0.016). We conclude that
oral vitamin C supplements are delivered to the brain, and speculate
that the increased CSF:plasma ratio of vitamin C in AD reflects
increased antioxidant consumption by the AD brain.
Pages 315-322
Danielle Laurin, René Verreault, Joan Lindsay, Éric Dewailly, Bruce
J. Holub
Omega-3 fatty acids and risk of cognitive impairment and dementia
Abstract: It has been suggested that the dietary intake of
omega-3 polyunsaturated fatty acids could be inversely related to
the risk of dementia and cognitive decline. This analysis examined
the association between plasma concentration of omega-3
polyunsaturated fatty acids and prevalence and incidence of
cognitive impairment and dementia. Data are reported on subjects 65
years or older who had a complete clinical evaluation at the first
two waves (1991-92 and 1996-97) of the Canadian Study of Health and
Aging. Main outcome measures were cognitive impairment and dementia
by mean relative plasma concentrations of fatty acids in the
phospholipid fraction at baseline. Results were adjusted for age,
sex, education, smoking, alcohol intake, body mass index, history of
cardiovascular disease, and apolipoprotein E e4 genotype. In the
cross-sectional analysis, no significant difference in omega-3
polyunsaturated fatty acid concentrations was observed between
controls and both prevalent cases of cognitive impairment and
dementia. In the prospective analysis, a higher eicosapentaenoic
acid (p < 0.01) concentration was found in cognitively impaired
cases compared to controls while higher docosahexaenoic acid (p <
0.07), omega-3 (p < 0.04) and total polyunsaturated fatty acid (p <
0.03) concentrations were found in dementia cases. These findings do
not support the hypothesis that omega-3 polyunsaturated fatty acids
play a protective role in cognitive function and dementia.
Pages 323-327
Thomas B. Shea and Daniela Ortiz
17 ß-Estradiol alleviates synergistic oxidative stress
resulting from folate deprivation and amyloid-ß treatment
Abstract: Oxidative stress is thought to be a pivotal
factor in Alzheimer’s disease (AD). Amyloid-ß (Aß) induces oxidative
damage, which is likely to be compounded by deficiencies in
endogenous antioxidant capacity. Indeed, folate deprivation, which
has been associated with AD, potentiates generation of reactive
oxygen species (ROS) by Aß. We examined whether the antioxidant
17-ß-estradiol could attenuate ROS generation following Aß treatment
in the presence and absence of folate using differentiated SH-SY-5Y
human neuroblastoma cells. Folate-deprivation and Aß treatment each
induced an increase in ROS, and treatment of folate-deprived
cultures with Aß induced a synergistic increase in ROS.
17-ß-estradiol reduced ROS levels in Aß-treated, folate-deprived
cultures to ROS levels observed in cultures treated with Aß in the
presence of folate, suggesting that this antioxidant was able to
prevent the synergistic impact of Aß and folate deprivation on ROS
generation. 17-ß-estradiol also completely prevented neuronal death
induced by both Aß and folate deprivation individually, and reduced
neuronal death following Aß treatment along with folate deprivation.
These findings suggest that therapeutic approaches utilizing
antioxidants may be particularly important in conditions such as AD,
where multiple factors, including compromises in endogenous
antioxidants, promote oxidative stress.
Pages 329-335
Anthony C. B. Lim, Robert Z. Qi
Cyclin-dependent kinases in neural development and
degeneration
Abstract: There is increasing evidence suggesting that
cyclin-dependent kinases (Cdks) that normally regulate cell cycle
progression may also be involved in the pathogenesis of
neurodegenerative disorders and in the apoptotic death of neurons
subjected to various insults. Deregulation of Cdks has been observed
in an increasing number of neurological disorders, including
Alzheimer’s and Parkinson’s diseases as well as amyotrophic lateral
sclerosis (ALS). Unchecked expression of these proteins can potently
induce apoptotic or necrotic neuronal cell death. Cdks initiate
death pathways by derepressing E2F-1/pRb-dependent transcription at
neuronal G1/S checkpoint. On the contrary, deregulation of Cdk5,
which is not involved in cell cycle control, contributes to
neurodegeneration by altering the phosphorylation state of
non-membrane-associated proteins. This review describes work
indicating Cdks’ roles in the nervous system and how they may
cogitate in leading neurons to their demise.
Pages 337-341
Transcript of Live Discussion held at the
Alzheimer Research Forum
Alzheimer Genes in Cortical Development: How Do Their
Prenatal Functions Relate to Dementia?
Pages 343-344
Book Review: Walking One Another Home: Moments of Grace and
Possibility in the Midst of Alzheimer’s by Rita Bresnahan. Ligouri/Triumph
(Ligouri, Missouri), 2003, 151pp. Reviewed by Grace Petot.
RETURN
TO INDEX
top |