Journal of Alzheimer's Disease - Volume 27, issue 2

Authors: Yang, Kai | Belrose, Jillian | Trepanier, Catherine H. | Lei, Gang | Jackson, Michael F. | MacDonald, John F.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia characterized by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. The mechanisms leading to AD are not completely understood; however, recent evidence suggests that alterations in Fyn, a Src family kinase, might contribute to AD pathogenesis. A number of studies have demonstrated that Fyn is involved in synaptic plasticity, a cellular mechanism for learning and memory. In addition, Fyn plays a role in the regulation of Aβ production and mediates Aβ-induced synaptic deficits and neurotoxicity. Fyn also induces tyrosine phosphorylation of tau. Although many studies have implicated a role …for Fyn in AD, the precise cellular and molecular mechanisms require further investigation. Novel insights into the role of Fyn in AD may help identify alternative pharmacological approaches for the treatment of AD. Show more

Keywords: Alzheimer's disease, AMPA receptors, amyloid-β, Fyn, NMDA receptors, synaptic plasticity, tau

DOI: 10.3233/JAD-2011-110353

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 243-252, 2011

Authors: Ortez, Carlos | Villar, Cristina | Fons, Carmen | Duarte, Sofía T. | Pérez, Ana | García-Villoria, Judith | Ribes, Antonia | Ormazábal, Aida | Casado, Mercedes | Campistol, Jaume | Vilaseca, Maria Antonia | García-Cazorla, Angels

Article Type: Short Communication

Abstract: 17β-hydroxysteroid dehydrogenase 10 (HSD10) deficiency is a rare X-linked inborn error of isoleucine catabolism. Although this protein has been genetically implicated in Alzheimer's disease pathogenesis, studies of amyloid-β peptide (Aβ) in patients with HSD10 deficiency have not been previously reported. We found, in a severely affected child with HSD10 deficiency, undetectable levels of Aβ in the cerebrospinal fluid, together with low expression of brain-derived neurotrophic factor, α-synuclein, and serotonin metabolites. Confirmation of these findings in other patients would help elucidating mechanisms of synaptic dysfunction in this disease, and highlight the role of Aβ in both early and late periods of …life. Show more

Keywords: Amyloid-β peptide, cerebrospinal fluid, childhood, HSD10 deficiency, inborn errors of metabolism, neurotransmitters, synaptic proteins

DOI: 10.3233/JAD-2011-110647

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 253-257, 2011

Authors: Mielke, Michelle M. | Haughey, Norman J. | Bandaru, Veera Venkata Ratnam | Weinberg, Danielle D. | Darby, Eveleen | Zaidi, Noman | Pavlik, Valory | Doody, Rachelle S. | Lyketsos, Constantine G.

Article Type: Research Article

Abstract: Plasma sphingolipids have been shown to predict cognitive impairment and hippocampal volume loss, but there is little research in patients with Alzheimer's disease (AD). In this study we sought to determine whether plasma ceramides, dihydroceramides (DHCer), sphingomyelins (SM), or dihydrosphingomyelin (DHSM) levels and ratios of SM/ceramide or DHSM/DHCer were predictive of progression in AD. Probable AD patients (n = 120) were enrolled in the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine. Plasma sphingolipids were assessed using ESI/MS/MS. Linear mixed effects models were used to examine the relation between baseline plasma sphingolipid levels and cross-sectional and longitudinal …performance on the Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating-Sum of Boxes (CDR-Sum). Participants were followed a mean of 4.2 visits and 2.3 years. There were no cross-sectional associations. In longitudinal analyses, high levels of DHCer and ceramide were associated with greater progression, but findings did not reach significance (p > 0.05). In contrast, higher plasma levels of SM, DHSM, SM/ceramide, and DHSM/DHCer ratios were associated with less progression on the MMSE and ADAS-Cog; the ratios were the strongest predictors of clinical progression. Compared to the lowest tertiles, the highest tertiles of DHSM/DHCer and SM/ceramide ratios declined 1.35 points (p = 0.001) and 1.19 (p = 0.004) points less per year on the MMSE and increased 3.18 (p = 0.001) and 2.42 (p = 0.016) points less per year on the ADAS-Cog. These results suggest that increased SM/ceramide and DHSM/DHCer ratios dose-dependently predict slower progression among AD patients and may be sensitive blood-based biomarkers for clinical progression. Show more

Keywords: Alzheimer's disease, biomarker, ceramide, dihydroceramide, sphingosine, dihydrosphingomyelin, plasma, sphinganine, sphingomyelin

DOI: 10.3233/JAD-2011-110405

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 259-269, 2011

Authors: Takasaki, Junichi | Ono, Kenjiro | Yoshiike, Yuji | Hirohata, Mie | Ikeda, Tokuhei | Morinaga, Akiyoshi | Takashima, Akihiko | Yamada, Masahito

Article Type: Research Article

Abstract: Inhibition of amyloid-β (Aβ) aggregation is an attractive therapeutic strategy for treatment of Alzheimer's disease (AD). We previously reported that vitamin A and β-carotene inhibit fibrillation of Aβ40 and Aβ42 (Ono et al, 2004, Exp Neurol). In this study, we firstly examined the effects of vitamin A (retinoic acid, retinol, and retinal), β-carotene, vitamin B2, vitamin B6, vitamin C, vitamin E, coenzyme Q10, and α-lipoic acid on oligomerization of Aβ40 and Aβ42 in vitro; vitamin A and β-carotene dose-dependently inhibited oligomerization of Aβ40 and Aβ42 . Furthermore, retinoic acid decreased cellular toxicity by inhibition of …Aβ42 oligomerization. Second, we analyzed how vitamin A inhibits Aβ aggregation by using fluorescence spectroscopy and thioflavin T assay with two Aβ fragments, Aβ1-16 and Aβ25-35 . A fluorescence peak of retinoic acid was greatly restrained in the presence of Aβ25-35 , and retinoic acid inhibited aggregation of Aβ25-35 , but not of Aβ1-16 , which suggest the specific binding of retinoic acid to the C-terminal portion of Aβ. Thus, vitamin A and β-carotene might be key molecules for prevention of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, oligomer, vitamin A

DOI: 10.3233/JAD-2011-110455

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 271-280, 2011

Authors: Li, Chuanming | Wang, Jian | Gui, Li | Zheng, Jian | Liu, Chen | Du, Hanjian

Article Type: Research Article

Abstract: Gray matter volume and density of several brain regions, determined by magnetic resonance imaging (MRI), are decreased in Alzheimer's disease (AD). Animal studies have indicated that changes in cortical area size is relevant to thinking and behavior, but alterations of cortical area and thickness in the brains of individuals with AD or its likely precursor, mild cognitive impairment (MCI), have not been reported. In this study, 25 MCI subjects, 30 AD subjects, and 30 age-matched normal controls were recruited for brain MRI scans and Functional Activities Questionnaire (FAQ) assessments. Based on the model using FreeSurfer software, two brain lobes were …divided into various regions according to the Desikan-Killiany atlas and the cortical area and thickness of every region was compared and analyzed. We found a significant increase in cortical area of several regions in the frontal and temporal cortices, which correlated negatively with MMSE scores, and a significant decrease in cortical area of several regions in the parietal cortex and the cingulate gyrus in AD subjects. Increased cortical area was also seen in some regions of the frontal and temporal cortices in MCI subjects, whereas the cortical thickness of the same regions was decreased. Our observations suggest characteristic differences of the cortical area and thickness in MCI, AD, and normal control subjects, and these changes may help diagnose both MCI and AD. Show more

Keywords: Alzheimer's disease, cortical area, cortical thickness, FreeSurfer, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-2011-110497

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 281-290, 2011

Authors: Vázquez-Higuera, José Luis | Mateo, Ignacio | Sánchez-Juan, Pascual | Rodríguez-Rodríguez, Eloy | Pozueta, Ana | Calero, Miguel | Dobato, José Luis | Frank-García, Ana | Valdivieso, Fernando | Berciano, José | Bullido, Maria J. | Combarros, Onofre

Article Type: Research Article

Abstract: Tau abnormal hyperphosphorylation and the formation of neurofibrillary tangles in the Alzheimer's disease (AD) brain is the result of upregulation of tau kinases. In a group of 729 Spanish late-onset AD patients and 670 healthy controls, we examined variations into a set of 20 candidate genes of kinases involved in tau phosphorylation at AD-related sites (PRKACB; CAMK2A; MARK1, 2, 3 and 4; CSNK1D; CDC2; RPS6KB1 and 2; p38α and β; IB1; JNK1, 2 and 3; MEK1 and 2; ERK1 and 2), to address hypotheses of genetic variation that might influence both AD risk and age at disease onset. There was …an increased frequency of RPS6KB2 (intron 2, rs917570) minor allele in patients (50%) versus controls (39%) (OR = 1.52; 95% CI 1.30–1.77; p = 1.24 × 10−5 Bonferroni corrected), and the presence of this minor allele was significantly (p = 4.2 × 10−5 ) associated with a 3-years later onset of AD (mean age 74.1 years) when compared to age at onset of non-minor allele carriers (mean age 71.1 years). In APOE non-ε4 allele carriers, the combined effect of AD-associated risk alleles from the genes of CDC2, RPS6KB1 and 2, p38α, JNK (1, 2 and 3), MEK2, and ERK2 was significantly (p = 0.002) associated with a late-onset (>76 years) of AD. The CDC2 AGC haplotype derived from SNPs in introns 3 (rs2448347), 5 (rs2456772), and 7 (rs1871447) showed a protective effect against AD in APOE non-ε4 allele carriers (permutation p = 1.0 × 10−4 ) with a frequency of 9% in cases and 15% in controls. Common genetic variation in the tau kinases pathway does underlie individual differences not only in susceptibility to AD but also in disease phenotype (age at disease onset). Show more

Keywords: Alzheimer's disease, kinases, phosphorylation, polymorphism, tau

DOI: 10.3233/JAD-2011-110794

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 291-297, 2011

Authors: Shi, Min | Sui, Yu-Ting | Peskind, Elaine R. | Li, Ge | Hwang, HyeJin | Devic, Ivana | Ginghina, Carmen | Edgar, John Scott | Pan, Catherine | Goodlett, David R. | Furay, Amy R. | Gonzalez-Cuyar, Luis F. | Zhang, Jing

Article Type: Research Article

Abstract: Phosphorylation of tau protein is a critical event in the pathogenesis of Alzheimer's disease (AD). Increased phosphorylated tau and total tau levels, combined with reduced concentrations of amyloid-β 1–42 (Aβ42 ) in cerebrospinal fluid (CSF), but not in plasma or serum, have been generally accepted as sensitive AD diagnostic markers. However, obtaining CSF is a relatively invasive procedure that requires participation of specially trained medical professionals, i.e., CSF is not an ideal sample source for screening or early diagnosis of AD, which is essential to current and future neuroprotective treatments for the disease. Here, we identified tau, but not Aβ …species, with mass spectrometry in human saliva, a body fluid that is much more accessible compared to CSF or even blood. Quantitative assessment of salivary levels of total tau, phosphorylated tau, and Aβ42 using highly sensitive Luminex assays revealed that, while Aβ42 was not detectable, the phosphorylated tau/tau ratio significantly increased in patients with AD compared to healthy controls. These results suggest that salivary tau species could be ideal biomarkers for AD diagnosis, especially at early stages of the disease or even screening asymptomatic subjects, allowing for a much larger therapeutic window for AD patients. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, saliva, tau protein

DOI: 10.3233/JAD-2011-110731

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 299-305, 2011

Authors: Koutras, Carolina | Lessard, Christian B. | Lévesque, Georges

Article Type: Research Article

Abstract: Presenilin-1 (PS1) is a broadly expressed transmembrane protein that is often mutated in familial Alzheimer's disease (AD). In addition to its role in amyloid production, PS1 interacts with several protein partners, including the neural plakophilin-related armadillo protein (NPRAP or δ-catenin). Although studies have suggested that NPRAP affects cell adhesion, other data suggest that it can modulate gene expression. To investigate the transcriptional effects of NPRAP, we over-expressed NPRAP and measured gene expression using a microarray. We found that multiple genes, including BCHE, which has been linked to AD, were regulated by NPRAP. Furthermore, we showed that NPRAP nuclear translocation was …required for gene regulation. Our results implicate NPRAP as a brain-specific signaling molecule with distinct roles at the cell junction and the nucleus. Show more

Keywords: Alzheimer's disease, butyrylcholinesterase, NPRAP/delta catenin, presenilin

DOI: 10.3233/JAD-2011-110536

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 307-316, 2011

Authors: Gao, Baobing | Long, Zhimin | Zhao, Lei | He, Guiqiong

Article Type: Research Article

Abstract: Amyloid plaques in the brains are the pathological hallmark of Alzheimer's disease (AD). Amyloid-β (Aβ), the central component of amyloid plaques, is generated from amyloid-β protein precursor (AβPP), following β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is still unknown and there has been no effective treatment for AD. Clinical data showed that brain cerebral perfusion of most AD patients was reduced before memory and cognitive impairment incurred. Hypoxia is the direct consequence of hypoperfusion. Improving oxygen supply in the brain might exert potential effective influence on AD pathology. Normobaric hyperoxia (NBO), in addition to serving …as a tool for enhancement of oxygen delivery, was protective in recent experimental and clinical pilot studies as well. In the present study, we evaluated the potential neuroprotective effects of NBO on behavioral deficits and neuropathology in AD. Morris water maze tests showed that NBO treatment notably improved the spatial learning and memory deficits in AβPP/PS1 transgenic mice. Immunohistochemical and thioflavin S staining showed that NBO treatment significantly decreased Aβ deposition and neuritic plaques formation in the cortex and hippocampus of AβPP/PS1 transgenic mice. Immunoblotting and ELISA assay revealed that NBO treatment reduced Aβ production by inhibiting γ-secretase cleavage of AβPP. Our study suggests that NBO may have a potential therapeutic effect at the early stage of AD. Show more

Keywords: Alzheimer's disease, amyloid-β, normobaric hyperoxia, senile plaques

DOI: 10.3233/JAD-2011-110308

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 317-326, 2011

Authors: de Wilde, Martijn C. | Penke, Botond | van der Beek, Eline M. | Kuipers, Almar A.M. | Kamphuis, Patrick J. | Broersen, Laus M.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Substantial evidence suggests a role for nutrition in the management of AD and especially suggests that interventions with combinations of nutrients are more effective than single-nutrient interventions. The specific multi-nutrient combination Fortasyn™Connect (FC), shown to improve memory in AD, provides phosphatide precursors and cofactors and is designed to stimulate the formation of phospholipids, neuronal membranes, and synapses. The composition comprises nucleotides, omega-3 polyunsaturated fatty acids (n3 PUFA), choline, B-vitamins, phospholipids, and antioxidants. The current study explored the protective properties of FC in …a membrane toxicity model of AD, the amyloid-β 1–42 (Aβ42 ) infused rat, which shows reduced exploratory behavior in an Open Field and impaired cholinergic functioning. To this end, rats were fed an FC enriched diet or a control diet and five weeks later infused with vehicle or Aβ42 into the lateral ventricle. Ten weeks post-infusion Aβ42 -rats fed the FC diet showed increased membrane n3 PUFA and phosphatidylcholine content while they did not show the reductions in exploratory behavior or in choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunoreactivity that were seen in Aβ42 -rats fed the control diet. We conclude that FC protects the cholinergic system against Aβ42 -induced toxicity and speculate that the effects of FC on membrane formation and composition might be supportive for this protective effect. Based on these data a long-term intervention study was started in the prodromal stages of AD (NTR1705, LipiDiDiet, EU FP7). Show more

Keywords: Alzheimer's disease, amyloid-β, cholinergic markers, dietary intervention, dietary precursors, membrane, nutrition, protection

DOI: 10.3233/JAD-2011-110635

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 327-339, 2011