Journal of Alzheimer's Disease - Volume 9, issue 1

Authors: Gong, Cheng-Xin | Liu, Fei | Grundke-Iqbal, Inge | Iqbal, Khalid

Article Type: Research Article

Abstract: Neurofibrillary degeneration characterized by abnormal hyperphosphorylation and aggregation of tau in affected neurons is directly associated with dementia symptoms and plays a pivotal role in the pathogenesis of Alzheimer disease (AD) and related tauopathies. It is well established that brain glucose uptake/metabolism is impaired in AD, but how this impairment contributes to the disease is unknown. We recently found that tau in human brain is also modified by O-GlcNAcylation in addition to phosphorylation and that the former negatively regulates the latter. On the basis of these findings, we propose a novel hypothesis that the impaired glucose uptake/metabolism contributes to AD …by facilitating abnormal hyperphosphorylation of tau. Further studies of this mechanism are likely to offer a novel therapeutic target for preventing and treating AD. Show more

Keywords: Alzheimer disease, tau, O-GlcNAcylation, phosphorylation, glucose uptake/metabolism, neurofibrillary degeneration, tauopathies

DOI: 10.3233/JAD-2006-9101

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 1-12, 2006

Authors: Lester-Coll, Nataniel | Rivera, Enrique J. | Soscia, Stephanie J. | Doiron, Kathryn | Wands, Jack R. | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: The cascade of Alzheimer's disease (AD) neurodegeneration is associated with persistent oxidative stress, mitochondrial dysfunction, impaired energy metabolism, and activation of pro-death signaling pathways. More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the insulin and insulin-like growth factor (IGF) genes and their corresponding receptors. We now demonstrate using an in vivo model of intracerebral Streptozotocin (ic-STZ), that chemical depletion of insulin and IGF signaling mechanisms combined with oxidative injury is sufficient to cause AD-type neurodegeneration. The ic-STZ-injected rats did not have elevated blood glucose levels, …and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss, gliosis, and increased immunoreactivity for p53, actived glycogen synthase kinase 3β, phospho-tau, ubiquitin, and amyloid-β. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes. Show more

Keywords: Diabetes, insulin, alzheimer's disease, glycogen synthase kinase, growth factor receptors, RT-PCR, streptozotocin

DOI: 10.3233/JAD-2006-9102

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 13-33, 2006

Authors: Joseph, J.A. | Fisher, D.R. | Bielinski, D.

Article Type: Research Article

Abstract: Previous research has indicated that selective vulnerability to oxidative stress may be important in determining regional differences in functional declines in neuronal aging. Oxidative stress vulnerability may involve selective deficits in Ca2+ buffering (Ca2+ recovery time following oxotremorine application) to oxidative stress, determined in-part by receptor subtype with M1, M2 and M4 AChR showing greater oxidative stress-induced loss [via dopamine (DA) exposure for 4 hrs] of Ca2+ recovery time than that seen in M3 or M5 cells. Deficits were antagonized by pre-treating M1, M2, or M4 AChR-transfected cells with blueberry (BB) extract. Thus, we assessed whether these …differences in oxidative stress vulnerability might involve differential patterns of DA-induced protein kinase (PKCα, PKCγ) and/or cyclic AMP response element binding protein (CREB) activation, and whether these differences might be altered by BB treatment. M1 or M3 AChR-transfected COS-7 cells were exposed to 1 mM DA, and activation of phospho-(p) mitogen-activated protein kinase (MAPK) signaling was examined by immunoblotting analyses. The results showed that DA increased pCREB and pPKCγ for both M1- and M3-transfected cells, and BBs decreased these DA-induced alterations, when measured by immunoblotting techniques. Taken together these findings suggest that M1/M3 oxidative stress sensitivity differences may involve differential signaling in pMAPK and pCREB under oxidative stress conditions, suggesting that the native protection in these receptors against oxidative stress and inflammation may be derived from reduced activation. These findings also suggest that BB may antagonize oxidative stress effects induced by DA in M1-transfected cells by lowering activation of pCREB, and possibly pPKCγ. Show more

Keywords: Muscarinic receptors, aging, MAPK, oxidative stress, blueberry

DOI: 10.3233/JAD-2006-9103

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 35-42, 2006

Authors: Chuu, Jenny Y-J | Taylor, Joy L. | Tinklenberg, Jared | Noda, Art | Yesavage, Jerome | Murphy Jr., Greer M.

Article Type: Research Article

Abstract: It is largely unknown why some patients with Alzheimer's disease (AD) decline cognitively more rapidly than others. Genetic differences among patients could influence rate of decline. Brain-derived neurotrophic factor (BDNF) is a neurotrophin important in the survival neurons and in memory function. BDNF levels are reduced in the brain in AD. The Val66Met polymorphism in the BDNF gene modifies neuronal BDNF secretion, and affects hippocampal function and memory performance. We tested the hypothesis that the BDNF Val66Met polymorphism influences rate of cognitive decline in AD. In a sample of 149 AD patients followed for an average of 3.9 years, we …found no effect of BDNF Val66Met genotype on rate of change in the Mini Mental State Examination. Results were similar when we excluded patients taking an acetylcholinesterase inhibitor, those placed in a nursing home during the study, or those with a neuropathological diagnosis that included AD plus an entity other than AD. We also found no evidence that the effects of the BDNF Val66Met genotype depend on APOE genotype, which itself had no effect on rate of cognitive change. These findings suggest that the functional BDNF Val66Met variant is not a major determinant of rate of cognitive decline in AD. Show more

Keywords: Alzheimer's disease, brain-derived neurotrophic factor, Mini Mental State Examination, cognitive decline, Apolipoprotein E, single nucleotide polymorphism, genotype

DOI: 10.3233/JAD-2006-9104

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 43-49, 2006

Authors: Grammas, Paula | Samany, Pezhman Ghatreh | Thirumangalakudi, Lakshmi

Article Type: Research Article

Abstract: The notion that microvascular abnormalities contribute to deleterious changes in the Alzheimer's disease (AD) brain is supported by work from our laboratory and others demonstrating biochemical and functional alterations of the microcirculation in AD. The objective of this study is to determine whether levels of neurotoxic (thrombin) and inflammatory (interleukin 8 (IL-8), integrins αV β3 and αV β5 ) proteins are altered in microvessels isolated from AD patients compared to levels in vessels obtained from non-demented age-matched controls. We also evaluate in AD and control microvessels expression of the transcription factor hypoxia-inducible factor 1-α(HIF1-α), which regulates pro-inflammatory gene expression, …and the regulation of HIF1-α expression by thrombin in cultured brain endothelial cells. Our results indicate that in AD there are high levels of expression of the neurotoxic protease thrombin and the inflammation-associated proteins IL-8 and αV β3 and αV β5 integrins. HIF1-α is higher in AD microvessels compared to control and thrombin treatment of cultured brain endothelial cells results in increased expression of HIF1-α. These data suggest that in AD the cerebral microcirculation is a source of neurotoxic and inflammatory mediators and as such contributory to pathologic processes ongoing in the AD brain. Show more

Keywords: Microvessels, neurotoxin, inflammation, vascular

DOI: 10.3233/JAD-2006-9105

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 51-58, 2006

Authors: Origlia, Nicola | Capsoni, Simona | Domenici, Luciano | Cattaneo, Antonino

Article Type: Research Article

Abstract: A deficit in cortical cholinergic synaptic transmission is a common feature of cognitive and behavioral impairment observed in neurodegenerative pathologies. AD11 transgenic mice producing blocking antibodies against Nerve Growth Factor (NGF) are characterized by a progressive neurodegenerative phenotype defined by the deposition of amyloid peptide, intracellular neurofibrillary tangles and by a marked cholinergic depletion. We exploited AD11 mice to develop a functional assay to investigate the impact of cholinergic deficit on cortical synaptic plasticity impairment at different neurodegenerative stages. In particular, we investigated the time course of long–term potentiation (LTP) impairment in neocortex of AD11 mice and potential rescue by …acute pharmacological treatment with Acetylcholine (ACh) or the cholinergic agonist Galantamine (GAL). We showed that LTP starts being absent in AD11 mice at 2 months, an age corresponding to early neurodegenerative stage characterized by the first observed decrease in number of basal forebrain cholinergic neurons (BFCNs) without overt cortical neurodegeneration. We demonstrated that acute ACh or GAL treatment fully reverts LTP impairment in 2 month old AD11 mice. In contrast, cholinergic treatment failed to recover synaptic plasticity deficit in aged (9–10 months) AD11 mice characterized by a severe cortical neurodegeneration. Show more

Keywords: NGF deprivation, LTP, acetylcholine, galantamine, transgenic mice

DOI: 10.3233/JAD-2006-9106

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 59-68, 2006

Authors: Summers, William K.

Article Type: Research Article

Abstract: Congress and the FDA have strongly suggested that tranquilizers and antipsychotics not be used in agitated demented frail elderly patients. The medical profession has not moved away from the tradition of antipsychotic sedation of such patients. Use of ‘modern second generation low dose’ antipsychotics continue to be the standard of care. Propranolol, a non-selective β-blocker with good penetration of the CNS, is a reasonable and safe alternative to sedatives and antipsychotics. Anti-dementia drugs are complementary to propranolol. A case study which contrasts the two pharmacologic approaches is detailed. A method of estimating delirium-agitation risk in dementia patients (DRN …method) is described. Show more

DOI: 10.3233/JAD-2006-9107

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 69-75, 2006

Authors: Espinosa, Patricio S. | Kryscio, Richard J. | Mendiondo, Marta S. | Schmitt, Fred A. | Wekstein, David R. | Markesbery, William R. | Smith, Charles D.

Article Type: Research Article

Abstract: Objective: Larger brains may contain more neurons and synaptic connections, providing a greater reserve against cognitive decline in Alzheimer's disease (AD). Larger head circumference (HC) may therefore be associated with later detection and diagnosis of AD. We investigated HC in nondemented individuals and AD patients using cross-sectional and prospective analyses. Methods: The cross sectional analysis compared mean HC between 592 AD patients and 459 nondemented controls. Prospective analysis was based on the same initially normal controls who were followed longitudinally for conversion to dementia. Diagnosis of AD was made by neurologists using NINDS-ADRDA criteria. Results: When compared …to AD patients, controls had a significantly larger mean HC by 0.58 cm in men and by 0.31 cm in women, but these differences were no longer significant after adjustment for age and years of education. HC varied inversely with age and directly with years of education but did not vary with presence/absence of dementia in first-degree relatives or with apolipoprotein-E (ApoE) genotype. In the prospective analysis, the hazard ratio for time to conversion to AD was not significant for HC when adjusted for age at entry, ApoE allele status, family history of dementia, gender, and years of education. ApoE allele status, first degree relative with dementia, and baseline age conferred an increased risk for conversion to AD, consistent with other studies. Conclusions: We observed a smaller HC in AD patients compared to nondemented individuals, but AD per se accounted for little of this difference. HC was not a statistically significant predictor for conversion to AD in our longitudinal group. Show more

Keywords: Alzheimer's disease, cerebral reserve, risk factor, head circumference

DOI: 10.3233/JAD-2006-9108

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 77-80, 2006

Article Type: Correction

DOI: 10.3233/JAD-2006-9109

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 81-88, 2006

Article Type: Discussion

DOI: 10.3233/JAD-2006-9110

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 89-93, 2006

Article Type: Announcement

DOI: 10.3233/JAD-2006-9111

Citation: Journal of Alzheimer's Disease, vol. 9, no. 1, pp. 95-97, 2006