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

Authors: Schweinzer, Cornelia | Kober, Alexandra | Lang, Ingrid | Etschmaier, Karoline | Scholler, Monika | Kresse, Adelheid | Sattler, Wolfgang | Panzenboeck, Ute

Article Type: Research Article

Abstract: Impaired clearance of cerebral amyloid-β (Aβ) across the blood-brain barrier (BBB) may facilitate the onset and progression of Alzheimer's disease (AD). Additionally, experimental evidence suggests a central role for cellular cholesterol in amyloid-β protein precursor (AβPP) processing. The present study investigated whether brain capillary endothelial cells (BCEC; the anatomical basis of the BBB) are capable of endogenous AβPP synthesis and whether and to what extent AβPP synthesis and processing is under control of cellular cholesterol homeostasis. Intracellular cholesterol metabolism was pharmacologically manipulated by using natural and synthetic liver-X receptor (LXR) agonists. Using an in vitro model of the BBB consisting …of primary porcine BCEC (pBCEC), we demonstrate that endogenous full-length AβPP synthesis by pBCEC is significantly increased while the amount of cell-associated, amyloidogenic Aβ oligomers is decreased in response to 24(S)-hydroxycholesterol (24OH-C) or 27OH-C, TO901317, cholesterol, or simvastatin treatment. Oxysterols, as well as simvastatin, enhanced the secretion of non-amyloidogenic sAβPPα up to 2.5-fold. In parallel, LXR agonists reduced cholesterol biosynthesis by 30–80% while stimulating esterification (up to 2.5-fold) and efflux (up to 2.5-fold) of cellular cholesterol by modifying hydroxymethylglutaryl-CoA reductase (HMGCR), sterol regulatory element-binding protein (SREBP-2), acyl-CoA: cholesterol acyltransferase 2 (ACAT-2), and ATP binding cassette transporter A1 (ABCA1) expression levels. In a polarized in vitro model mimicking the BBB, pBCEC secreted sAβPPα preferentially to the basolateral compartment. In summary endothelial cells of the BBB actively synthesize AβPP, Aβ oligomers, and secrete AβPPα in a polarized manner. AβPP processing by pBCEC is regulated by LXR agonists, which have been proven beneficial in experimental AD models. Show more

Keywords: Alzheimer's disease, amyloid-β, blood-brain barrier, cholesterol, endothelial cells, liver-X receptors, oxysterols, statins

DOI: 10.3233/JAD-2011-110854

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 341-360, 2011

Authors: Hunter, Jesse M. | Bowers, William J. | Maarouf, Chera L. | Mastrangelo, Michael A. | Daugs, Ian D. | Kokjohn, Tyler A. | Kalback, Walter M. | Luehrs, Dean C. | Valla, Jon | Beach, Thomas G. | Roher, Alex E.

Article Type: Research Article

Abstract: Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been genetically altered with human familial AD genes driven by powerful promoters. However, a Tg model must accurately mirror the pathogenesis of the human disease, not merely the signature amyloid and/or tau pathology, as such hallmarks can arise via multiple convergent or even by pathogenic mechanisms unrelated to human sporadic AD. The 3 × Tg-AD mouse simultaneously expresses 3 rare familial mutant genes that in humans independently produce devastating amyloid-β protein precursor (AβPP), presenilin-1, and frontotemporal dementias; hence, technically speaking, these mice are not a model of sporadic AD, but are …informative in assessing co-evolving amyloid and tau pathologies. While end-stage amyloid and tau pathologies in 3 × Tg-AD mice are similar to those observed in sporadic AD, the pathophysiological mechanisms leading to these lesions are quite different. Comprehensive biochemical and morphological characterizations are important to gauge the predictive value of Tg mice. Investigation of AβPP, amyloid-β (Aβ), and tau in the 3 × Tg-AD model demonstrates AD-like pathology with some key differences compared to human sporadic AD. The biochemical dissection of AβPP reveals different cleavage patterns of the C-terminus of AβPP when compared to human AD, suggesting divergent pathogenic mechanisms. Human tau is concomitantly expressed with AβPP/Aβ from an early age while abundant extracellular amyloid plaques and paired helical filaments are manifested from 18 months on. Understanding the strengths and limitations of Tg mouse AD models through rigorous biochemical, pathological, and functional analyses will facilitate the derivation of models that better approximate human sporadic AD. Show more

Keywords: Alzheimer's disease, amyloid-β precursor protein, presenilin, tau, transgenic mice

DOI: 10.3233/JAD-2011-110608

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 361-376, 2011

Authors: Aerts, Marjolein B. | Esselink, Rianne A.J. | Claassen, Jugen A.H.R. | Abdo, Wilson Farid | Bloem, Bastiaan R. | Verbeek, Marcel M.

Article Type: Research Article

Abstract: Differentiating dementia with Lewy bodies (DLB) from Alzheimer's Disease (AD) can be difficult because of the substantial overlap in clinical features. Since deficits in serotonergic and dopaminergic pathways seem more pronounced in DLB patients, we investigated whether cerebrospinal fluid (CSF) analysis of neurotransmitter metabolites, in addition to brain-specific proteins, may improve the differentiation between DLB and AD. We retrospectively compared CSF concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and the brain-specific proteins total tau (t-tau), phosphorylated tau protein (p-tau), and amyloid-β42 (Aβ42 ) in 45 patients with AD (mean age 71.6 years; …34 (76%) men; 44 probable AD, 1 definite) and 23 patients with DLB (mean age 71.6 years; 18 (78%) men; 6 possible DLB, 16 probable, 1 definite). The concentrations of all neurotransmitter metabolites, as well as those for t-tau and p-tau protein, were significantly lower in DLB compared to AD, irrespective of the diagnostic certainty (i.e., possible or probable). The currently used combination of Aβ42 , p-tau, and t-tau yielded a sensitivity of 92.9% and a specificity of 90%. The addition of MHPG resulted in an increased sensitivity of 97.6% and a specificity of 95% for the discrimination between DLB and AD. In conclusion, the combination of MHPG and the brain specific proteins t-tau, p-tau, and Aβ42 in CSF were associated with the clinical diagnosis of DLB and discriminated between AD and DLB with high diagnostic accuracy, suggesting this combination as a potential biomarker for DLB. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, dementia with Lewy bodies, diagnosis, MHPG, neurotransmitter metabolites, tau

DOI: 10.3233/JAD-2011-110482

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 377-384, 2011

Authors: Matsuda, Shuji | Tamayev, Robert | D'Adamio, Luciano

Article Type: Research Article

Abstract: An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI , genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-β protein precursor (AβPP), a gene associated with Alzheimer's disease, which inhibits processing of AβPP. AβPP/Bri2 complexes are reduced in …synaptic membranes of FDDKI mice. Consequently, AβPP metabolites derived from processing of AβPP by β-, α-, and γ-secretases are increased in Danish dementia mice. AβPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AβPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AβPP and BRI2 functionally interact. Here, we have investigated whether AβPP processing is altered in FDD patients' brain samples. We find that the levels of several AβPP metabolites, including Aβ, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AβPP metabolites, suggesting that Familial Danish and Alzheimer's dementias share common pathogenic mechanisms. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, BRI2, familial danish dementia

DOI: 10.3233/JAD-2011-110785

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 385-391, 2011

Authors: Jessen, Frank | Lewczuk, Piotr | Gür, Okan | Block, Wolfgang | Ende, Gabriele | Frölich, Lutz | Hammen, Thilo | Arlt, Sönke | Kornhuber, Johannes | Kucinski, Thomas | Popp, Julius | Peters, Oliver | Maier, Wolfgang | Träber, Frank | Wiltfang, Jens

Article Type: Research Article

Abstract: The interplay of amyloid and mitochondrial function is considered crucial in the pathophysiology of Alzheimer's disease (AD). We tested the association of the putative marker of mitochondrial function N-acetylaspartate (NAA) as measured by proton magnetic resonance spectroscopy within the medial temporal lobe and cerebrospinal fluid amyoid-β42 (Aβ42 ), total Tau and pTau181. 109 patients were recruited in a multicenter study (40 mild AD patients, 14 non-AD dementia patients, 29 mild cognitive impairment (MCI) AD-type patients, 26 MCI of non-AD type patients). NAA correlated with Aβ42 within the AD group. Since the NAA concentration is coupled to neuronal mitochondrial …function, the correlation between NAA and Aβ42 may reflect the interaction between disrupted mitochondrial pathways and amyloid production. Show more

Keywords: Alzheimer's disease, amyloid-β42, N-acetylaspartate, medial temporal lobe, mitochondria, proton MR spectrocopy

DOI: 10.3233/JAD-2011-110398

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 393-399, 2011

Authors: Du, Xue-ting | Wang, Li | Wang, Yu-jiong | Andreasen, Maria | Zhan, Da-wei | Feng, Ying | Li, Min | Zhao, Min | Otzen, Daniel | Xue, Di | Yang, Yang | Liu, Rui-tian

Article Type: Research Article

Abstract: Amyloid-β (Aβ40/42 ) aggregates containing the cross-β-sheet structure are associated with the pathogenesis of Alzheimer's disease (AD). It is generally accepted that the N-terminal peptide of Aβ40/42 , Aβ1-16 , does not aggregate, and is not cytotoxic. However, we here show that Aβ1-16 can aggregate, and form cytotoxic aggregates containing β-turns and regular non-amyloid β-sheet structures. Factors such as pH, ionic strength, and agitation were found to influence Aβ1-16 aggregation, and the amino acid residues Asp1, His6, Ser8, and Val12 in Aβ1-16 may play a role in this aggregation. Our MTT results showed that Aβ1-16 monomers …or oligomers were toxic to SH-SY5Y cells, but Aβ1-16 fibrils exhibited less cytotoxicity. Our studies also indicate that Aβ1-16 aggregates can increase the formation of reactive oxygen species and nitric oxide, induce the loss of calcium homeostasis, and incur the microglial production of TNF-α and IL-4. Thus, our findings suggest that Aβ1-16 may contribute to AD pathogenesis. Show more

Keywords: Aggregation, Alzheimer's disease, amyloid-β, neurotoxicity

DOI: 10.3233/JAD-2011-110476

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 401-413, 2011

Authors: Threlkeld, Zachary D. | Jicha, Greg A. | Smith, Charles D. | Gold, Brian T.

Article Type: Research Article

Abstract: Reduced task deactivation within regions of the default mode network (DMN) has been frequently reported in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). As task deactivation reductions become increasingly used in the study of early AD states, it is important to understand their relationship to atrophy. To address this issue, the present study compared task deactivation reductions during a lexical decision task and atrophy in aMCI, using a series of parallel voxel-wise and region-wise analyses of fMRI and structural data. Our results identified multiple regions within parietal cortex as convergence areas of task deactivation and atrophy in aMCI. …Relationships between parietal regions showing overlapping task deactivation reductions and atrophy in aMCI were then explored. Regression analyses demonstrated minimal correlation between task deactivation reductions and either local or global atrophy in aMCI. In addition, a logistic regression model which combined task deactivation reductions and atrophy in parietal DMN regions showed higher classificatory accuracy of aMCI than separate task deactivation or atrophy models. Results suggest that task deactivation reductions and atrophy in parietal regions provide complementary rather than redundant information in aMCI. Future longitudinal studies will be required to assess the utility of combining task deactivation reductions and atrophy in the detection of early AD. Show more

Keywords: Alzheimer's disease, atrophy, deactivation, default mode network (DMN), mild cognitive impairment, voxel-based morphometry

DOI: 10.3233/JAD-2011-110206

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 415-427, 2011

Authors: Oliveira, Sandra Marisa | Ribeiro, Carlos A. | Cardoso, Isabel | Saraiva, Maria João

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder affecting tens of millions of people worldwide, with women being at greater risk of developing the disease. A growing body of evidence suggests transthyretin (TTR) as an important modulator of AD pathogenesis. Aiming at providing further insight into the potential neuroprotective role of TTR and gender differences in AD, we crossed transgenic AβPPswe/PS1A246E mice with TTR-null mice and investigated both male and female AβPPswe/PS1A246E/TTR+/+ , AβPPswe/PS1A246E/TTR+/- , and AβPPswe/PS1A246E/TTR-/- animals for brain amyloid-β (Aβ) levels and deposition. The levels of circulating TTR between non-transgenic and AD mice were evaluated. Decreased levels of …circulating TTR in AD mice as compared to non-transgenic littermates were observed in early stages of AD-like neuropathology, but not at later stages where an opposite relationship was found. Elevated brain levels of Aβ42 were observed in AβPPswe/PS1A246E/TTR+/- female mice as compared to AβPPswe/PS1A246E/TTR+/+ female littermates; no significant differences were found among males of different TTR genotypes. We subsequently quantified the brain levels of testosterone and 17β-estradiol in these animals and verified that AβPPswe/PS1A246E/TTR+/- female mice present reduced brain levels of both hormones as compared to AβPPswe/PS1A246E/TTR+/+ females; no significant differences were detected among males of different TTR genotypes. Our results provide evidence for a gender-associated modulation of brain Aβ levels and brain sex steroid hormones by TTR, and suggest that reduced levels of brain testosterone and 17β-estradiol in female mice with TTR genetic reduction might underlie their increased AD-like neuropathology. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, 17β-estradiol, testosterone, transgenic mouse, transthyretin

DOI: 10.3233/JAD-2011-110488

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 429-439, 2011

Authors: Kim, Woojin S. | Hill, Andrew F. | Fitzgerald, Michael L. | Freeman, Mason W. | Evin, Genevieve | Garner, Brett

Article Type: Research Article

Abstract: Cerebral amyloid-β (Aβ) deposition is a critical feature of Alzheimer's disease. Aβ is derived from the amyloid-β protein precursor (AβPP) via two sequential cleavages that are mediated by β-secretase and the γ-secretase complex. Such amyloidogenic AβPP processing occurs in lipid raft microdomains of cell membranes and it is thought that modulating the distribution of lipids in rafts may regulate AβPP processing and Aβ production. Certain ATP-binding cassette (ABC) transporters regulate lipid transport across cell membranes and, as recent studies reveal, within membrane microdomains. ABCA1 also regulates Aβ metabolism in the brain although its direct impact on AβPP remains an open …question. Here we assessed the capacity of three ABCA1 mutants (that do not promote lipid efflux) to modulate AβPP processing. Unexpectedly, these non-functional mutants also reduced Aβ production similar to wild type ABCA1. ABCA1 expression did not alter AβPP localization in lipid rafts, and co-immunoprecipitation experiments indicated ABCA1 and AβPP physically interact. These data suggest that ABCA1 may regulate AβPP processing independent of its impact on membrane lipid homeostasis. Show more

Keywords: ABCA1, AβPP processing, Alzheimer's disease, lipid transport, membrane biology, Tangier disease

DOI: 10.3233/JAD-2011-110521

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 441-452, 2011

Authors: Grambaite, Ramune | Selnes, Per | Reinvang, Ivar | Aarsland, Dag | Hessen, Erik | Gjerstad, Leif | Fladby, Tormod

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) may affect multiple neuropsychological domains. While amnestic MCI is associated with Alzheimer's disease, patterns of brain pathology in non-amnestic subtypes have been less studied. Twenty-three patients with attention/executive MCI (a/e MCI), seen at a university-based memory clinic, and 23 normal controls, matched according to age, gender, and education, were included in this study. All subjects were assessed with a neuropsychological test battery, including tests of memory, attention and executive function, and underwent magnetic resonance imaging. Diffusion tensor imaging derived white matter (WM) tract radial and mean diffusivity (DR and MD) were assessed using Tract-Based Spatial Statistics, …and cortical thickness (CTH) was assessed using FreeSurfer. This study investigated changes of WM DR/MD and CTH in subjects with a/e MCI, and associations between these changes and different a/e subfunctions. WM DR/MD underlying rostral middle frontal, medial orbitofrontal, caudal anterior cingulate, posterior cingulate, retrosplenial and entorhinal cortices was higher for the a/e MCI than the control group, but CTH was not different from controls in any of the regions. WM DR/MD underlying superior frontal, rostral middle frontal, lateral/medial orbitofrontal and retrosplenial cortices were significantly associated with inhibition/switching performance, while caudal middle frontal CTH was significantly associated with attention and divided attention in the patient group. We conclude that increased WM DR/MD in frontal and cingulate regions and cortical thinning in caudal middle frontal region are both associated with executive dysfunction in MCI. Show more

Keywords: Alzheimer's disease, cortical thickness, diffusion tensor imaging, mild cognitive impairment, radial and mean diffusivity, white matter

DOI: 10.3233/JAD-2011-110290

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 453-462, 2011

Article Type: Correction

DOI: 10.3233/JAD-2011-119001

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 463-463, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110291

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 465-466, 2011