Journal of Alzheimer's Disease - Volume 16, issue 3

Authors: Kifle, Lydia | Ortiz, Daniela | Shea, Thomas B.

Article Type: Research Article

Abstract: Increased homocysteine has in some cases been linked with an increased incidence of Alzheimer's disease and motor neuron disease. Folate or B12 deficiency increases homocysteine, but controversy exists as to whether their levels also correlate with either disorder. Since their presence within various dietary constituents may confound interpretation, we tested the impact of deprivation of either or both in the closed environment of neuronal cell cultures. Deprivation of either increased cytosolic calcium, reactive oxygen species, intracellular homocysteine, and apoptosis, but deprivation of both fostered substantially larger increases, supporting the notion that both are required for optimal neuroprotection.

Keywords: Alzheimer's disease, B12, folate, neurodegeneration, nutritional supplementation

DOI: 10.3233/JAD-2009-1006

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 533-540, 2009

Authors: Lopes, Joao P. | Blurton-Jones, Mathew | Yamasaki, Tritia R. | Agostinho, Paula | LaFerla, Frank M.

Article Type: Research Article

Abstract: Cell cycle proteins are elevated in the brain of patients and in transgenic models of Alzheimer's disease (AD), suggesting that aberrant cell cycle re-entry plays a key role in this disorder. However, the precise relationship between cell cycle reactivation and the hallmarks of AD, amyloid-β (Aβ) plaques and tau-laden neurofibrillary tangles, remains unclear. We sought to determine whether cell cycle reactivation initiates in direct response to Aβ and tau accumulation or whether it occurs as a downstream consequence of neuronal death pathways. Therefore, we used a triple transgenic mouse model of AD (3xTg-AD) that develops plaques and tangles, but does …not exhibit extensive neuronal loss, whereas to model hippocampal neuronal death a tetracycline-regulatable transgenic model of neuronal ablation (CaM/Tet-DTA mice) was used. Cell-cycle protein activation was determined in these two models of neurodegeneration, using biochemical and histological approaches. Our findings indicate that Cdk4, PCNA and phospho-Rb are significantly elevated in CaM/Tet-DTA mice following neuronal death. In contrast, no significant activation of cell-cycle proteins occurs in 3xTg-AD mice versus non-transgenic controls. Taken together, our data indicate that neuronal cell cycle reactivation is not a prominent feature induced by Aβ or tau pathology, but rather appears to be triggered by acute neuronal loss. Show more

Keywords: Alzheimer's disease, amyloid-β, apoptosis, Cdk4, cell cycle, PCNA, phospho-histone H3, phospho-Rb, tetracycline-inducible, transgenic mice

DOI: 10.3233/JAD-2009-0993

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 541-549, 2009

Authors: Miyoshi, Katsue | Ohyagi, Yasumasa | Sakae, Nobutaka | Motomura, Kyoko | Ma, Linqing | Taniwaki, Takayuki | Furuya, Hirokazu | Tabira, Takeshi | Kira, Jun-ichi

Article Type: Research Article

Abstract: Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease. Acceleration of apoptosis is one of the major pathogenic mechanisms of PS1 mutants, and PS1 mutants have also been reported to induce overproduction of amyloid-β protein 42. Here, we investigated aberrancy in activation of initiator caspases related to two PS1 gene mutations, I143T and G384A. Acceleration of apoptosis, elevation of caspase-3/7 activity, and significant increases in caspase-4, -8 and -9 activities during apoptosis induced by several agents were found in these mutant PS1-transfected cells. Interestingly, thapsigargin treatment enhanced caspase-4 and -9 activities in I143T-mutant PS1-transfected cells, …while hydrogen peroxide treatment enhanced caspase-4, -8 and -9 activities in G384A-mutant PS1-transfected cells, indicating diverse apoptosis-promoting effects of PS1 gene mutations. In addition, treatment with a β-secretase inhibitor or γ-secretase inhibitor significantly attenuated the effects of the PS1 mutants on caspase-3/7 activation and recovered cell viability. Our present data suggest that these PS1 mutants accelerate the activation of initiator caspases and promote apoptosis, which may be associated, at least in part, with amyloid-β production. Show more

Keywords: Alzheimer's disease, apoptosis, caspase, presenilin, β-secretase, γ-secretase

DOI: 10.3233/JAD-2009-0989

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 551-564, 2009

Authors: Ma, Linqing | Ohyagi, Yasumasa | Miyoshi, Katsue | Sakae, Nobutaka | Motomura, Kyoko | Taniwaki, Takayuki | Furuya, Hirokazu | Takeda, Kazuya | Tabira, Takeshi | Kira, Jun-ichi

Article Type: Research Article

Abstract: Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-β42 (Aβ42 ) production as well as to promote apoptosis. We have recently reported that intracellular Aβ42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels …in mutant PS1-transfected cells. Treatment with a β-secretase inhibitor and γ-secretase inhibitor decreased the intracellular Aβ levels in amyloid-β protein precursor (AβPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AβPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Aβ and proteasome impairment. Show more

Keywords: Alzheimer's disease, p53, presenilin, proteasome, β-secretase, γ-secretase

DOI: 10.3233/JAD-2009-0990

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 565-575, 2009

Authors: McClendon, McKee J. | Hernandez, Santiago | Smyth, Kathleen A. | Lerner, Alan J.

Article Type: Research Article

Abstract: The biological meaning of uncertain dementia ratings (CDR 0.5) and its treatment implications are unclear. Our study examines the frequency of anti-dementia medication use in individuals with CDR 0.5 and the cognitive, behavioral, and demographic factors associated with memantine and acetylcholinesterase inhibitor (AChEI) use. Subjects were drawn from the National Alzheimer Coordinating Center database, which collects data from 30 Alzheimer Disease Centers. There were 2,512 subjects with the following diagnoses: Normal, 11.8%; Mild cognitive impairment, 44.6%; Alzheimer's disease, 34.9%; and other dementias, 8.7%. Overall, 35% used AChEIs and 13% used memantine. AChEI and memantine use was greater in subjects who …were referred by clinics and diagnosed with Alzheimer's disease. AChEI use was associated with being married, younger, male, and more educated while memantine use was associated with less severe apathy and other dementia diagnosis. Non-Hispanic whites were more likely to use AChEI and memantine than non-Hispanic blacks (OR = 2.2, 2.5). Hispanics were more likely to use AChEI than non-Hispanic blacks. It appears anti-dementia medication use in CDR 0.5 is frequent and represents evidence for extensive off label usage. Diagnosis, severity of impairment, and race, among other variables, affect the likelihood of AChEI and memantine use in this population. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer's disease, CDR 0.5, disparity, ethnicity, memantine, mild cognitive impairment, off label, race

DOI: 10.3233/JAD-2009-0994

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 577-583, 2009

Authors: Tong, Ming | Dong, Matthew | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) frequently overlap with Alzheimer's disease, which is linked to brain impairments in insulin, insulin-like growth factor (IGF), and neurotrophin signaling. We explored whether similar abnormalities occur in PD or DLB, and examined the role of manganese toxicity in PD/DLB pathogenesis. Quantitative RT-PCR demonstrated reduced expression of insulin, IGF-II, and insulin, IGF-I, and IGF-II receptors (R) in PD and/or DLB frontal white matter and amygdala, and reduced IGF-IR and IGF-IIR mRNA in DLB frontal cortex. IGF-I and IGF-II resistance was present in DLB but not PD frontal cortex, and associated with reduced …expression of Hu, nerve growth factor, and Trk neurotrophin receptors, and increased levels of glial fibrillary acidic protein, α-synuclein, dopamine-β-hydroxylase, 4-hydroxy-2-nonenal (HNE), and ubiquitin immunoreactivity. MnCl2 treatment reduced survival, ATP, and insulin, IGF-I and IGF-II receptor expression, and increased α-synuclein, HNE, and ubiquitin immunoreactivity in cultured neurons. The results suggest that: 1) IGF-I, IGF-II, and neurotrophin signaling are more impaired in DLB than PD, corresponding with DLB's more pronounced neurodegeneration, oxidative stress, and α-synuclein accumulation; 2) MnCl2 exposure causes PD/DLB associated abnormalities in central nervous system neurons, and therefore may contribute to their molecular pathogenesis; and 3) molecular abnormalities in PD/DLB overlap with but are distinguishable from Alzheimer's disease. Show more

Keywords: Central nervous system, dementia with Lewy bodies, human, insulin-like growth factor resistance, neurotrophin, Parkinson's disease, receptor-ligand binding

DOI: 10.3233/JAD-2009-0995

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 585-599, 2009

Authors: Kester, Maartje I. | Blankenstein, Marinus A. | Bouwman, Femke H. | van Elk, Evert J. | Scheltens, Philip | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: The object of this study was to elucidate the effect of age in the relationship between APOE genotype and CSF biomarkers amyloid-β1–42 (Aβ42 ), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) in AD and controls. 302 AD patients and 174 controls were categorized into APOE ε4 carriers and non-carriers, and into younger and older (⩾65years). In controls, older age and APOE ε4 were independently associated with lower Aβ42 and higher tau and ptau-181 levels (p < 0.05). For tau and ptau-181, there were also interactions (p < 0.10): older carriers had higher levels than older …non-carriers, without effect for younger controls. In AD, APOE ε4 genotype had a main effect on Aβ42 , but there was also an interaction: older carriers had lower Aβ42 than older non-carriers, without effect for younger AD patients (p < 0.05). For tau and ptau-181, there were only interactions: older carriers had higher levels than older non-carriers, while younger AD patients showed the opposite (p ⩽ 0.05). Association between CSF biomarkers and APOE genotype were modified by age in both controls and AD patients. This suggests that cognitively healthy APOE ε4 carriers are more prone to develop AD pathology with aging. For AD patients, this provides support for the existence of subtypes within the disease. Show more

Keywords: Aging, Alzheimer's disease, APOE genotype, biomarkers, cerebrospinal fluid

DOI: 10.3233/JAD-2009-0999

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 601-607, 2009

Authors: Vardy, Emma R.L.C. | Rice, Penny J. | Bowie, Peter C.W. | Holmes, John D. | Catto, Andrew J. | Hooper, Nigel M.

Article Type: Research Article

Abstract: The insertion allele in the gene encoding angiotensin-converting enzyme (ACE) is a risk factor for Alzheimer's disease (AD) and ACE is one of several peptidases that have the ability to degrade the neurotoxic amyloid-β peptide. ACE is a membrane-bound peptidase that is also present in a soluble form in plasma as a result of a zinc metalloprotease-mediated shedding event. Here we aimed to determine whether there is a difference in ACE in the plasma of late-onset clinically diagnosed AD patients (n = 94) as compared to age-matched non-demented control subjects (n = 188). Plasma ACE was lower in the AD …subjects as compared to the controls both at baseline (p = 0.072) and after two years (p = 0.05). There was a greater reduction in plasma ACE in the AD subjects as compared to the control subjects over the two years. Plasma ACE did not correlate with cognitive function. The observed reduction in plasma ACE in AD may reflect a general decrease in the zinc metalloprotease-mediated shedding of a subset of membrane-bound proteins. Show more

Keywords: Alzheimer's disease, angiotensin-converting enzyme, apolipoprotein E, plasma, shedding, zinc metalloprotease

DOI: 10.3233/JAD-2009-1002

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 609-618, 2009

Authors: Run, Xiaoqin | Liang, Zhihou | Zhang, Lan | Iqbal, Khalid | Grundke-Iqbal, Inge | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Abnormal hyperphosphorylation and aggregation of microtubule-associated protein tau play a crucial role in neurodegeneration of Alzheimer's disease (AD). Anesthesia has been associated with cognitive impairment and the risk for AD. Here we investigated the effects of anesthesia on site-specific tau phosphorylation and the possible mechanisms. We found that anesthesia for short periods (30 sec to 5 min) induced tau phosphorylation at Thr181, Ser199, Thr205, Thr212, Ser262, and Ser404 to small, but significant, extents, which appeared to result from anesthesia-induced activation of stress-activated protein kinases. Anesthesia for a longer time (1 h) induced much more dramatic phosphorylation of tau at the …above sites, and the further phosphorylation may be associated with hypothermia induced by anesthesia. Anesthesia-induced tau phosphorylation appears to be specific because the increased phosphorylation was only seen at half of the tau phosphorylation sites studied and was not observed in global brain proteins. These studies clarified the dynamic changes of tau phosphorylation at various sites and, thus, served as a fundamental guide for future studies on tau phosphorylation by using brains of anesthetized experimental animals. Our findings also provide a possible mechanism by which anesthesia may cause postoperative cognitive impairment and increase the risk for AD. Show more

Keywords: Alzheimer's disease, anesthesia, phosphorylation, tau, tau kinases, tau phosphatases

DOI: 10.3233/JAD-2009-1003

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 619-626, 2009

Authors: Grünblatt, Edna | Bartl, Jasmin | Zehetmayer, Sonja | Ringel, Thomas M. | Bauer, Peter | Riederer, Peter | Jacob, Christian P.

Article Type: Research Article

Abstract: Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. At present, diagnosis of AD is rather late in the disease. Therefore, we attempted to find peripheral biomarkers for the early diagnosis of AD. We investigated the profiles of 33 genes, previously found by our group to have altered expression in postmortem brains of AD. The gene profiles were studied via quantitative-real-time-reverse-transcription-polymerase-chain-reaction, in whole blood samples (collected with the PAXgene™ blood RNA system) isolated from a population clinically diagnosed with AD and healthy controls (1-year period/ up to 4 samples). Five genes showed significant correlation to …the dementia score, Mini-Mental State Examination (MMSE). Focusing on the two genes with the smallest p-value, H3-histone and cannabinoid-receptor-2, notable increases in these genes were found in peripheral blood mRNA in subjects with lower MMSE scores. Seasonal variations in gene expression were not significant due to sample size, but did seem to vary due to time of sample withdrawal. In conclusion, gene expression profiling might be a promising method to investigating a large population with the aim of developing an early diagnosis of AD. Show more

Keywords: Alzheimer's disease, biomarker, cannabinoid receptor, diagnose, gene expression, histone

DOI: 10.3233/JAD-2009-0996

Citation: Journal of Alzheimer's Disease, vol. 16, no. 3, pp. 627-634, 2009