Journal of Alzheimer's Disease - Volume 5, issue 4

Authors: Gillett, M.J. | Martins, R.N. | Clarnette, R.M. | Chubb, S.A.P. | Bruce, D.G. | Yeap, B.B.

Article Type: Research Article

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 (Aβ40, 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 Aβ40. These data demonstrate that lower androgen levels are associated with increased plasma Aβ40 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 Aβ40, warranting further investigation. Show more

Keywords: testosterone, sex hormone binding globulin, amyloid beta peptide 40, memory loss, dementia, men

DOI: 10.3233/JAD-2003-5401

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 267-269, 2003

Authors: Petanceska, Suzana S.

Article Type: Article Commentary

DOI: 10.3233/JAD-2003-5402

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 271-273, 2003

Authors: Rhodin, Johannes A. | Thomas, Tom N. | Clark, Linda | Garces, Amanda | Bryant, Margaret

Article Type: Research Article

Abstract: Vascular dysfunction and inflammatory processes may be early events in the pathology of Alzheimer's disease (AD). Even though amyloid β-peptides (Aβ) play a prominent role in the initiation and progression of cellular dysfunction in AD, the precise in vivo actions of various Aβ-peptides has not been established. The cerebrovascular actions of the major Aβ-peptides (1–40) and (1–42) in live animals were investigated using an open cranial window technique. We show here that the Aβ-peptides cause vascular lesions, especially in the arterioles. In one set of experiments, leukocytes and platelets were tagged with Rhodamine 6G, soluble Aβ(1–40) infused intravenously for 2 …minutes, and the vasculature video recorded for 90 minutes. In a second set of experiments, soluble Aβ(1–40) infusion was followed 30 minutes later by an infusion of soluble Aβ(1–42) and the vasculature recorded for 90 minutes. Fluorescent and transmission electron microscopic examinations demonstrated the following cerebrovascular action of Aβ-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 Aβ(1–40) and (1–42) produced significantly more vascular disruption than Aβ(1–40) alone. Oral administration of conjugated estrogens in ovariectomized female rats protected them from the deleterious actions of Aβ-peptides. The reported protective effect of estrogen against AD may be mediated in part through prevention of cerebrovascular Aβ toxicity. Show more

Keywords: Alzheimer's disease, amyloid β-proteins, inflammation, leukocyte-platelet-endothelial interaction, thrombosis, conjugated estrogens, cranial window technique

DOI: 10.3233/JAD-2003-5403

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 275-286, 2003

Authors: Smith, Julie Vining | Luo, Yuan

Article Type: Research Article

Abstract: The role of amyloid β-peptide (Aβ) 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 Aβproduction to study the effects of Aβ 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 Aβ when stimulated, as well as transgenic Caenorhabditis elegans constitutively expressing human Aβ. A rise in levels of hydrogen peroxide (H2 O2 ) was observed in both in vitro and …in vivo AD-associated transgenic models expressing the Aβ 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 H2 O2 -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 H2 O2 -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 Aβ and ROS in association with AD. Show more

Keywords: Reactive oxygen species, Ginkgo biloba, Amyloid β, Alzheimer's disease, Caenorhabditis elegans

DOI: 10.3233/JAD-2003-5404

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 287-300, 2003

Authors: Pérez, Mar | Hernández, Félix | Lim, Filip | Díaz-Nido, Javier | Avila, Jesús

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, glycogen synthase kinase 3, lithium, neurodegeneration, protein aggregation, tauopathy

DOI: 10.3233/JAD-2003-5405

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 301-308, 2003

Authors: Quinn, Joseph | Suh, Jung | Moore, M. Milar | Kaye, Jeffrey | Frei, Balz

Article Type: Research Article

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. Show more

DOI: 10.3233/JAD-2003-5406

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 309-313, 2003

Authors: Laurin, Danielle | Verreault, René | Lindsay, Joan | Dewailly, Éric | Holub, Bruce J.

Article Type: Research Article

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 (1991–1992 and 1996–1997) 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. Show more

Keywords: dementia, omega-3 fatty acids, eicosapentaenoic acid, docosahexaenoic acid

DOI: 10.3233/JAD-2003-5407

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 315-322, 2003

Authors: Shea, Thomas B. | Ortiz, Daniela

Article Type: Research Article

Abstract: Oxidative stress is thought to be a pivotal factor in Alzheimer's disease (AD). Amyloid-β (Aβ) 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 Aβ. We examined whether the antioxidant 17-β-estradiol could attenuate ROS generation following Aβ treatment in the presence and absence of folate using differentiated SH-SY-5Y human neuroblastoma cells. Folate-deprivation and Aβ treatment each induced an increase in ROS, and treatment of folate-deprived cultures with Aβ induced a synergistic increase in ROS. 17-β-estradiol reduced ROS …levels in Aβ-treated, folate-deprived cultures to ROS levels observed in cultures treated with Aβ in the presence of folate, suggesting that this antioxidant was able to prevent the synergistic impact of Aβ and folate deprivation on ROS generation. 17-β-estradiol also completely prevented neuronal death induced by both Aβ and folate deprivation individually, and reduced neuronal death following Aβ 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. Show more

Keywords: oxidative stress, antioxidants, estradiol, folate Aβ, Alzheimer's disease

DOI: 10.3233/JAD-2003-5408

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 323-327, 2003

Authors: Lim, Anthony C.B. | Qi, Robert Z.

Article Type: Research Article

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. Show more

Keywords: cyclin-dependent kinases, cell cycle, neuronal development, degeneration

DOI: 10.3233/JAD-2003-5409

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 329-335, 2003

Article Type: Discussion

DOI: 10.3233/JAD-2003-5410

Citation: Journal of Alzheimer's Disease, vol. 5, no. 4, pp. 337-341, 2003