Journal of Alzheimer's Disease - Volume 4, issue 6

Authors: Levin-Allerhand, Justine A. | Lominska, Chris E. | Wang, Jennifer | Smith, Jonathan D.

Article Type: Research Article

Abstract: Post-menopausal estrogen therapy is associated with a decreased incidence of Alzheimer disease and in vitro models have shown that 17β-estradiol is effective in lowering amyloidogenic processing. To examine the effects of estrogen withdrawal and replacement on amyloid β (Aβ) levels and amyloidβ-protein precursor (AβPP) processing in vivo, Swedish mutant AβPP transgenic mice were ovariectomized or sham ovariectomized at four weeks of age and treated with placebo or 17β- or 17α-estradiol pellets, the latter being a weak estrogen receptor agonist. Compared to sham ovariectomized mice, ovariectomy with placebo did not alter Aβ levels; however, the levels of Aβ were decreased by …27% with 17β- and 17α- estradiol, respectively, with no change in AβPP holoprotein. Endogenous and exogenous estrogen both significantly increased the levels of sAβPPα, the secreted form of AβPP. The ratio of Aβ/sAβPPα, a measure of amyloidogenic processing, was reduced in all estrogen-containing groups. The Aβ lowering effect of 17β- and 17α-estradiol was replicated when estrogens were administered at a more physiological dose in the drinking water, or when mice were ovariectomized at three months of age. The increased efficacy of 17α-estradiol versus 17β-estradiol may help to develop safe and effective therapeutics. Show more

DOI: 10.3233/JAD-2002-4601

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 449-457, 2002

Authors: Zambenedetti, Pamela | Schmitt, Horst P. | Zatta, Paolo

Article Type: Research Article

Abstract: Binswanger's disease is a subacute form of hypertensive encephalopathy characterized by patchy-confluent myelin loss of the deep hemispheric white matter, associated with marked regressive changes of the oligodendrocytes and variable astroglial reaction. To understand the distribution and the specificity of astrocyte pathology in Binswanger's disease we quantified reactive and degenerating astrocytes in different regions of the deep and subcortical white matter and of the cerebral cortex. Sections of frontal, temporal, parietal, and occipital lobes of 12 histologically proven cases of Binswanger's disease were immunostained with antibodies to glial fibrillary protein (GFAP) and to metallothionein I and II (MT-I-II), markers which …specifically identify normal and reactive astrocytes. Control tissues were from 6 elderly patients without neurological diseases. The brains of Binswanger's disease were characterized by few and lightly immunostained astrocytes in the deep white matter, but normal and reactive astrocytes, strongly immunoreactive for GFAP and MT-I-II, were prominent in the subcortical white matter and the cerebral cortex. However, the relative distribution of GFAP positive and MT-I-II positive astrocytes was significantly different between the cerebral cortex and the subcortical white matter, the MT-I-II positive astrocytes being more frequent in the cerebral cortex, and the GFAP positive astrocytes in the subcortical white matter (p < 0.02). The GFAP and MT-I-II expressions in subsets of reactive astrocytes in the cortico-subcortical layers together with regressive astroglial changes in the deep white matter suggest that the dynamic plasticity of astroglia is topographically and biochemically differentiated in vascular dementia of Binswanger type. Show more

Keywords: binswanger disease, cerebrovascular diseases, Alzheimer disease, metallothionein, white matter, astrocytosis

DOI: 10.3233/JAD-2002-4602

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 459-466, 2002

Authors: Khalil, Zeinab | Poliviou, Helen | Maynard, Christa J. | Beyreuther, Konrad | Masters, Colin L. | Li, Qiao-Xin

Article Type: Research Article

Abstract: Freshly prepared soluble amyloid (Aβ) peptide has been reported to have vascular actions both in vitro and in vivo. This study was designed to examine the in vivo microvascular effects ofβ in two skin microvascular model systems that might reflect possible short and long-term vascular effects of this peptide. Short-term vascular effects were examined using freshly prepared soluble Aβ(1-40) peptide superfused over naive rat skin microvasculature for 15 min. Peripheral microvascular functional changes in 9-months-old transgenic (Tg) mice overexpressing solubleβ in the brain, peripheral circulation and other tissues, were also examined. Microvascular responses were monitored using laser Doppler flowmetry from …the base of a blister raised on the hind footpad of the animals. Endothelial-dependent and independent vasodilatation responses (VD) were examined using acetylcholine (ACh) and sodium nitroprusside (SNP) respectively. The exposure of naïve rat skin microvasculature to Aβ(1-40) resulted in an immediate vasoconstriction (VC) that prevented ACh but not SNP from inducing a subsequent VD response. The vascular effects of Aβ(1-40) were reversed by antioxidants (superoxide dismutase and catalase) and an endothelin A (ETA) receptor antagonist (BQ-123). Tg mice overexpressing soluble Aβ and C100 showed significant reductions in both endothelial-dependent and endothelial-independent VD that were also reversed by antioxidants and BQ-123. In conclusion, this study provided evidence to support the notion of peripheral vascular effects of Aβ in vivo and present novel evidence for alterations in endothelial and smooth muscle cell function in peripheral skin microvasculature in Tg mice overexpressing Aβ and C100. We suggest that skin microvasculature is a useful model to examine the mechanisms underlying the vascular actions of the Aβ protein. Show more

Keywords: Amyloid β-peptide, skin microvasculature, endothelial cell function, endothelin, reactive oxygen species, transgenic mouse, Alzheimer's disease

DOI: 10.3233/JAD-2002-4603

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 467-478, 2002

Authors: Bozner, Peter | Wilson, G. Lee | Druzhyna, Nadya M. | Bryant-Thomas, Tara K. | LeDoux, Susan P. | Wilson, Glenn L. | Pappolla, Miguel A.

Article Type: Research Article

Abstract: Patients with Down syndrome (DS) and Alzheimer's disease (AD) share a number of characteristic neuropathologic lesions. Several lines of evidence suggest that mitochondria and the oxidative stress response are involved in the pathogenesis of both conditions. In the process of investigating the stress response in DS, we discovered a defective basal expression of a major mitochondrial heat shock protein, chaperonin 60 (Cpn60) in non-transformed dermal fibroblast cell lines from DS individuals. Such a defect was not present in control cells that had been cultured under identical physiological growth conditions. A quantitative analysis by Western blots showed a marked reduction of …Cpn60 per equal amount of total protein in DS cells to an average of 35% showed a marked reduction of the mRNA signal for Cpn60 in all the DS cell lines. To gain further information, experiments were conducted to study the rate of de-novo synth esis of Cpn60 at normal and supraoptimal temperatures in DS and controls. Results showed no significant differences between the two study groups. HSP60 is important in mitochondrial function and defects in these organelles have been reported in DS and AD. Thus, the findings may have potential implications in the neuropathology of DS. Show more

Keywords: chaperonin 60, Down's syndrome, heat shock protein 60, heat shock proteins, trisomy 21

DOI: 10.3233/JAD-2002-4604

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 479-486, 2002

Authors: Perry, TracyAnn | Greig, Nigel H.

Article Type: Research Article

Abstract: Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an insulinotropic hormone, secreted from the enteroendocrine L cells of the intestinal tract in response to nutrient ingestion. It enhances pancreatic islet β-cell proliferation and glucose-dependent insulin secretion, and lowers blood glucose in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. The chemoarchitecture of receptor distribution in the brain correlates well with a central role for GLP-1 in the regulation of food intake and response to aversive stress. We have recently reported that GLP-1 and several …longer acting analogs that bind at the GLP-1 receptor, possess neurotrophic properties, and offer protection against glutamate-induced apoptosis and oxidative injury in cultured neuronal cells. Furthermore, GLP-1 can modify processing of the amyloid β- protein precursor in cell culture and dose-dependently reduces amyloid β-peptide levels in the brain in vivo. As such, this review discusses the known role of GLP-1 within the central nervous system, and considers the potential of GLP-1 and analogs as novel therapeutic targets for intervention in Alzheimer's disease (AD) and potentially other central and peripheral neurodegenerative conditions. Show more

DOI: 10.3233/JAD-2002-4605

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 487-496, 2002

Authors: de la Torre, J.C.

Article Type: Research Article

Abstract: Presently, non-genetic Alzheimer's disease (AD) is wrongly classified as a neurodegenerative disorder. When vascular lesions are present, AD is considered to be a vascular dementia. However, compelling evidence indicates that (AD) is a vascular disorder with neurodegenerative consequences. There is an urgent clinical need to ascertain the true cause of this dementia. In this review, evidence indicating that AD is a vascular disorder comes from a number of different disciplines including studies in epidemiology, pharmacology, neuroimaging, clinical medicine, pathology, physiology and experimental research. This collective evidence also addresses many previously puzzling questions regarding: i) past and present treatment failures …in AD, ii) strange association of AD risk factors with many vascular-related disorders, iii) parallel lesions, clinical symptoms risk factors and potentially interchangeable treatments present in AD and vascular dementia, iv) historical difficulty in finding neurodegenerative markers to detect AD pre-clinivally, and, v) paradoxical pathophysiologic events preceding AD neurodegenerative changes. Re-classifying AD as a vascular disorder would very likely improve the chances of finding a useful treatment for this disorder because clinical study designs could focus on more realistic and relevant pathologic targets than is presently practiced. A short summary of potential new research lines that may provide novel therapy in the treatment and management of AD is discussed. Show more

DOI: 10.3233/JAD-2002-4606

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 497-512, 2002

Authors: Aliev, Gjumrakch

Article Type: Research Article

DOI: 10.3233/JAD-2002-4607

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 513-516, 2002

Authors: Polidori, M. Cristina | Mecocci, Patrizia

Article Type: Research Article

Abstract: Oxidative stress is believed to play a major role in the pathogenesis of Alzheimer disease (AD). Plasma concentrations of vitamins C, A and E, of uric acid, thiols and carotenoids were lower and of malondialdehyde (MDA) higher in 35 AD patients (85.9 ± 5.5 y) compared to 40 controls 85.5 ± 4.4 y) . Differences were significant for vitamin C, vitamin E, lutein, lycopene, α-carotene and MDA (p < 0.001). Plasma exposed to peroxyl radicals showed a rate of antioxidant consumption and of MDA production higher in AD patients than in controls. AD in advanced age is accompanied by a …poor plasma antioxidant status and increased plasma lipid peroxidation, as well as by a low resistance to peroxyl radical exposure. Show more

Keywords: Alzheimer dementia, antioxidants, AAPH, oxidative stress, aging

DOI: 10.3233/JAD-2002-4608

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 517-522, 2002

Authors: Sparks, D. Larry | Lochhead, Jeff | Horstman, Donna | Wagoner, Tom | Martin, Tim

Article Type: Research Article

Abstract: Increased circulating cholesterol is known to promote risk of coronary artery disease. It is now emerging that cholesterol promotes production and accumulation of amyloid β (Aβ) deposited in the hallmark pathologic lesion of Alzheimer's disease (AD), the senile plaque, perhaps by shifting away from normal metabolism of amyloid β protein precursor (AβPP) to β. Previous studies employing the cholesterol-fed rabbit model of AD demonstrated that induction of AD-like Aβaccumulation in brain could be reversed by co-administration of cholesterol lowering drugs or removing cholesterol, prompted initiation of an AD Cholesterol-Lowering (Statin) Treatment Trial. We now present data that identify a previously …unrecognized role for dietary water quality on the severity of neuropathology induced by elevated cholesterol. Neuronal accumulation of Aβ induced by increased circulating concentrations of cholesterol in the New Zealand white rabbit is attenuated when distilled drinking water is administered compared to use of tap water. The numbers of neurons in cholesterol-fed rabbits that exhibited Aβ immunoreactivity, relative to normal chow-fed controls, increased ∼ 2.5 fold among animals on tap water but only ∼ 1.9 fold among animals on distilled water. This yielded a statistically significant ∼ 28% water. In addition, the subjectively assessed intensity of neuronalβ immunoreactivity was consistently reduced among cholesterol-fed rabbits allowed distilled drinking water compared to cholesterol-fed rabbits on tap water. As intensity of antibody immunoreactivity is likely related to concentration of antigen, the identified difference among cholesterol-fed rabbits allowed distilled drinking water may hold greater importance than a significant reduction in numbers of affected neurons. The effect on neuronalβ immunoreactivity intensity was observable among cholesterol-fed rabbits reared and allowed tap water when performing studies in three distinct locales. Pilot data suggest the possibility of increased clearance of Aβ from the brain, identified as increased blood levels, among cholesterol-fed rabbits administered distilled water compared to animals on tap water. The agent(s) occurring in tap water, excluded by distillation, promoting accumulation of neuronal Aβ immunoreactivity is(are) yet undisclosed, but arsenic, manganese, aluminum, zinc, mercury, iron and nitrate have tentatively been excluded because they were not identifiable (below detection limits) in the tap water of the three locales where the cholesterol-induced neuropathologic difference was observable. These findings suggest that water quality may impact on human health in the setting of increased circulating cholesterol levels, and could illustrate a truly simple life-style change that could be of benefit in AD. Show more

Keywords: Alzheimer's pathology, cholesterol, water quality

DOI: 10.3233/JAD-2002-4609

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 523-529, 2002

Authors: Moalem, Sharon | Percy, Maire E.

Article Type: Research Article

Abstract: Modern science has embraced reductionism, seeking ever-smaller parts to explain the whole. Although reductionistic approaches are successful in very simple biological modelling, they are not necessarily appropriate for systems of increasing complexity. Drawing on famous historical examples of how non-reductionist thinking has benefited mankind, and of how reductionism has sometimes led to erroneous conclusions, we call attention to the need to move away from purely linear reasoning in order to succeed in addressing many of the problems we face with the predicted demographic increase in seniors, and the increase in numbers of those afflicted with Alzheimer disease. The time has …come to reconsider and seriously question our most basic assumptions and beliefs surrounding what we believe Alzheimer disease to be, without which we run the risk of missed opportunities and failure. Show more

DOI: 10.3233/JAD-2002-4610

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 531-537, 2002

Article Type: Other

DOI: 10.3233/JAD-2002-4611

Citation: Journal of Alzheimer's Disease, vol. 4, no. 6, pp. 539-539, 2002