Journal of Alzheimer's Disease - Volume 11, issue 1

Authors: Perry, George | Smith, Mark A.

Article Type: Editorial

DOI: 10.3233/JAD-2007-11101

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 1-1, 2007

Authors: Wischik, Claude M.

Article Type: Obituary

DOI: 10.3233/JAD-2007-11102

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 3-5, 2007

Authors: Wischik, Claude M.

Article Type: Other

DOI: 10.3233/JAD-2007-11103

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 7-9, 2007

Article Type: Other

DOI: 10.3233/JAD-2007-11104

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 11-11, 2007

Authors: Wang, Suqing | Simon, Brook P. | Bennett, David A. | Schneider, Julie A. | Malter, James S. | Wang, Deng-Shun

Article Type: Research Article

Abstract: Pin1 protein, a peptidyl-prolyl cis-trans isomerase plays an important regulatory role in neuronal function. Recent studies indicate that Pin1 may promote the dephosphorylation of tau and restore its ability to bind to and polymerize microtubles. Previous studies on postmortem human brains showed that Pin1 is down-regulated in advanced Alzheimer's disease (AD) brains compared to age-matched non-demented controls. Because AD is a slowly progressive disease with a preclinical period that can last years, the abundance and regulatory function of Pin1 may vary on the course of the disease. In order to evaluate the potential contribution of Pin1 to AD pathogenesis, levels …of mRNA, protein and isomerase activity of Pin1 and phosphorylated tau from postmortem brains of 10 persons with mild-cognitive impairment (MCI), 10 with AD and 10 age-matched no cognitive impairment (NCI) were measured. The relationship between Pin1 and phosphorylated tau as well as clinical and cognitive data were analyzed. The results indicated that Pin1 activity in MCI and AD were significantly higher than in NCI. Phosphorylated tau in MCI and AD was also higher than in NCI group. The positive correlation trend in MCI and the robust correlation in AD between Pin1 activity and phosphorylated tau implies that increasing phosphorylated tau during AD pathogenesis may induce the compensatory activation/up-regulation of Pin1, while the inverse correlation between Pin1 activity and phosphorylated tau in NCI group implies that decreased Pin1 may play a role in the initial accumulation of phosphorylated tau in AD pathogenesis. Show more

Keywords: Alzheimer's disease, Pin1, tau, cognitive, dementia, MCI, AD

DOI: 10.3233/JAD-2007-11105

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 13-23, 2007

Authors: Khalil, Z. | LoGiudice, D. | Khodr, B. | Maruff, P. | Masters, C.

Article Type: Research Article

Abstract: Background: The concept that the neurotoxicity of amyloid β protein could partly result from vascular effects that may be detected in peripheral microcirculation is new. Methods: We compared peripheral endothelial vascular responses of patients with early clinically confirmed Alzheimer’s disease (AD) to that of people with normal cognition and those with other forms of dementia. Acetylcholine (ACh) was iontophoresed into the skin and the resultant vasodilator response was measured using laser Doppler flowmetery. Results: The ratio of ACh response to saline (ratio E/S) was determined. Mean ± SEM of ratios E/S were 8.8 ± 0.9 …for controls (n = 168 ), 1.4 ± 0.1 for AD patients (n = 80 ) and 3.1 ± 0.5 for other dementia (n = 84 ). Using the optimal cut-off point of E/S ratio of 1.9, an 80% diagnostic sensitivity and specificity for AD have been observed. When the control sample was filtered for those with cardiovascular diseases and with MMSE < 28, this improved the specificity to 90% (n = 119 ). Furthermore, 15 subjects were randomly drawn from a longitudinal healthy ageing study. Five of those subjects met the criteria for mild cognitive impairment (MCI) after eight years of follow up using a battery of cognitive tests. When tested for their E/S ratio in a blind fashion, the skin test successfully identified those subjects. Conclusions: The results support our hypothesis that endothelial alterations can be detected early in the course of the disease. We suggest that this simple skin test could potentially be applied as diagnostic adjunct in patients with mild cognitive symptoms or those with early clinical evidence of AD. Show more

DOI: 10.3233/JAD-2007-11106

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 25-32, 2007

Authors: Drago, Denise | Folin, Marcella | Baiguera, Silvia | Tognon, Giuseppe | Ricchelli, Fernanda | Zatta, Paolo

Article Type: Research Article

Abstract: Metal ions are widely recognized as a key factor for the conformational changes and aggregation of the Alzheimer's disease amyloid (Aβ). So far Al3+ has received much less attention than other biometals in terms of interaction with Aβ. Brain endothelial cells have been identified as important regulators of the neuronal microenvironment, including Aβ levels. The purpose of this study is to compare the effects of the complex amyloid (Aβ1-42 )-Al, from human and rat, with the effects produced by metal-free Aβ on rat neuroendothelial cells (NECs). To establish Aβ and Aβ-Al toxicity on NECs, survival, vitality, and angiogenesis are …evaluated. Cell survival is reduced by human and rat Aβ in a time-dependent manner. This toxic effect is remarkably pronounced in the presence of human Aβ-Al. Moreover, rat Aβ has anti-angiogenic properties on NECs, and this effect is aggravated dramatically by using both human and rat Aβ-Al complexes. The data and arguments presented herein clearly demonstrate the involvement of Al3+ in Aβ aggregation and, consequently, increasing endothelial cell toxicity. Show more

Keywords: Alzheimer, amyloid, aluminum, metal ions, blood-brain barrier, endothelial cells

DOI: 10.3233/JAD-2007-11107

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 33-44, 2007

Authors: Strum, Jay C. | Shehee, Ron | Virley, David | Richardson, Jill | Mattie, Michael | Selley, Paula | Ghosh, Sujoy | Nock, Christina | Saunders, Ann | Roses, Allen

Article Type: Research Article

Abstract: Rosiglitazone was found to simulate mitochondrial biogenesis in mouse brain in an apolipoprotein (Apo) E isozyme-independent manner. Rosiglitazone induced both mitochondrial DNA (mtDNA) and estrogen-stimulated related receptor alpha (ESRRA) mRNA, a key regulator of mitochondrial biogenesis. Transcriptomics and proteomics analysis suggested the mitochondria produced in the presence of human ApoE3 and E4 were not as metabolically efficient as those in the wild type or ApoE knockout mice. Thus, we propose that PPARγ agonism induces neuronal mitochondrial biogenesis and improves glucose utilization leading to improved cellular function and provides mechanistic support for the improvement in cognition observed in treatment of Alzheimer's …patients with rosiglitazone. Show more

Keywords: Mitochodrial biogenesis, PPARγ Alzheimer's Disease, rosiglitazone, real time PCR

DOI: 10.3233/JAD-2007-11108

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 45-51, 2007

Authors: Gómez-Ramos, Pilar | Asunción Morán, M.

Article Type: Research Article

Abstract: Autopsied brain tissue from Alzheimer's disease patients and old non-demented controls was studied after immunocytochemistry with the 4G8 monoclonal antibody that recognizes amyloid-β peptides. Intraneuronal 4G8-positive reaction product was detected in all of the studied brains. The same brain regions in the Alzheimer's disease samples consistently showed both more immunopositive neurons and more stained reaction product per neuron than those from the non-demented brains. Ultrastructurally, the immunopositive reaction product accumulated in clusters of cytoplasmic elements that had a lipofuscin-like appearance, showed a fibrogranular content and were also closely apposed to lipid droplets located either on their periphery or within them. …The most strongly 4G8-immunopositive elements had diffuse limits with their fibrogranular content free in the cytoplasm, whereas elements either without or showing only light immunoreaction had a limiting membrane. All immunopositive neurons displayed a similar pattern of clumping heterochromatin. The hypothetical neurotoxic role of intraneuronal amyloid-β peptides free in the cytoplasm is discussed as is the possible relationship between the amyloid-β peptides recognized by the 4G8 antibody and the lipid droplets which would presumably contain esterified cholesterol. Show more

Keywords: Alzheimer disease, intraneuronal amyloid-β peptides, neurotoxicity, lipid droplet, cholesterol

DOI: 10.3233/JAD-2007-11109

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 53-59, 2007

Authors: Head, E. | Lott, I.T. | Patterson, D. | Doran, E. | Haier, R.J.

Article Type: Research Article

Abstract: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. …Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population. Show more

DOI: 10.3233/JAD-2007-11110

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 61-76, 2007

Authors: Liu, Hsiu-Chih | Wang, Hsiao-Chien | Ko, Shun-Yao | Wang, Pei-Ning | Chi, Chin-Wen | Hong, Chen-Jee | Lin, Ker-Neng | Liu, Tsung-Yun

Article Type: Research Article

Abstract: This study analyzed whether platelet amyloid β-protein precursor (AβPP) isoform ratio correlates with cognition or cognitive decline in patients with Alzheimer's disease (AD). Platelet AβPP isoform ratio was measured, and cognitive assessment was performed using the Mini-Mental State Examination (MMSE) in 66 AD patients at baseline (T0) and in 29 of these patients in a one-year follow-up (T1). There was a significant correlation between the AβPP isoform ratios and MMSE scores in the 66 AD patients at T0. The T1 subjects were divided into two groups: 12 “no decliners” (MMSE score, T1–T0 ⩾ 0) and 17 “decliners” (MMSE score, T1–T0 …< 0). The decliners group showed a significantly greater reduction of AβPP isoform ratio from T0 to T1 than the no decliners group. However, the decline of the ratio did not correlate with the decline of MMSE score. These findings indicate that AβPP isoform ratio correlates with cognition, and reduction in this ratio may be a marker for cognitive decline in AD patients. Show more

Keywords: Alzheimer's disease, platelet, amyloid β-protein precursor (AβPP), AβPP isoform ratio, and Mini-Mental State Examination (MMSE)

DOI: 10.3233/JAD-2007-11111

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 77-84, 2007

Authors: Henriques, Ana Gabriela | Vieira, Sandra Isabel | Rebelo, Sandra | Domingues, Sara C.T.S. | da Cruz e Silva, Edgar F. | da Cruz e Silva, Odete A.B.

Article Type: Research Article

Abstract: Alzheimer's amyloid-β protein precursor (AβPP) can occur in different isoforms, among them AβPP751 , which is the most abundant isoform in non-neuronal tissues, and AβPP695 , often referred to as the neuronal isoform. However, few isoform-specific roles have been addressed. In the work here described, AβPP isoforms, both endogenous and as cDNA fusions with green fluorescent protein (GFP), were used to permit isoform-specific monitoring in terms of intracellular processing and targeting. Differences were particularly marked in the turnover rates of the immature isoforms, with AβPP751 having a faster turnover rate than AβPP695 (0.8 h and 1.2 h respectively …for endogenous proteins and 1.1 h and 2.3 h for transfected proteins). Hence, AβPP751 matures faster. Additionally, AβPP751 responded to both okadaic acid (OA) and phorbol 12-myristate 13-acetate (PMA), as determined by sAβPP production, with PMA inducing a more robust response. For the AβPP695 isoform, however, although PMA produced a strong response, OA failed to elicit such an induction in sAβPP production, implicating isoform specificity in phosphorylation regulated events. In conclusion, it seems that the AβPP695 isoform is processed/metabolized at a slower rate and responds differently to OA when compared to the AβPP751 isoform. The relevance of isoform-specific processing in relation to Alzheimer's disease needs to be further investigated, given the predominance of the AβPP695 isoform in neuronal tissues and isoform-specific alterations in expression levels associated with the pathology. Show more

Keywords: AβPP isoforms, okadaic acid, phorbol esters, AβPP targeting, phosphorylation

DOI: 10.3233/JAD-2007-11112

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 85-95, 2007

Authors: Jacob, C.P. | Koutsilieri, E. | Bartl, J. | Neuen-Jacob, E. | Arzberger, T. | Zander, N. | Ravid, R. | Roggendorf, W. | Riederer, P. | Grünblatt, E.

Article Type: Research Article

Abstract: Excitatory neurotransmitter dysfunction has been discussed to be involved in the pathophysiology of Alzheimer's disease (AD). In the current study we investigated gene and protein expression patterns of glutamatergic receptors and transporters in brains of AD patients in various stages of disease using gene chip arrays, real time PCR and immunohistochemistry. We found marked impairment in the expression of excitatory amino acid transporters (EAAT1 and EAAT 2) at both gene and protein levels in hippocampus and gyrus frontalis medialis of AD patients, already in early clinical stages of disease. The loss of EAAT immunoreactivity was particularly obvious in the vicinity …of amyloid plaques. In contrast, EAAT expression was up-regulated in the cerebellum of these patients. Furthermore, a significant up-regulation of the glutamatergic kainate (GRIK4) receptor observed by gene arrays was confirmed by quantitative RT-PCR in late stages in the hippocampus of AD patients. Moreover, there were down-regulations of other glutamatergic receptors such as NMDA (GRINL1A) and AMPA (GRIA4) receptors. Our data show marked changes in the functional elements of the glutamatergic synapses such as glutamatergic receptors and transporters and indicate impaired glutamate clearing rendering neurons susceptible to excess extracellular glutamate and support further the involvement of excitotoxic mechanisms in the pathogenesis of AD. Show more

Keywords: Alzheimer's disease, array, gene expression, glutamate, kainate, quantitative PCR

DOI: 10.3233/JAD-2007-11113

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 97-116, 2007

Authors: Santos, Alexander Navarrete | Torkler, Sandra | Nowak, Denny | Schlittig, Claudia | Goerdes, Mirjam | Lauber, Thomas | Trischmann, Lothar | Schaupp, Michael | Penz, Monika | Tiller, Friedrich-Wilhelm | Böhm, Gerald

Article Type: Research Article

Abstract: The neuropathology of Alzheimer's disease (AD) has been linked recently to non-fibrillar forms of neurotoxic amyloid-β (Aβ) oligomers of which high levels are observed in the brain of AD patients. This suggests that Aβ oligomers play a key role in the early events of AD, underlining their potential for the early diagnosis of the disease. We have developed an extremely sensitive assay for the detection of oligomeric and fibrillar structures of Aβ that is based on multiparametric analysis of data obtained by flow cytometry and fluorescence resonace energy transfer (Fret). The assay readily detects Aβ oligomers in human cerebrospinal fluid …(CSF) as verified by dot blot of the isolated particles. By measuring 174 CSF samples of non-demented control patients with various neurological disorders a high reliability and reproducibility of the method could be demonstrated. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, cerebrospinal fluid, flow cytometry, fluorescence resonance energy transfer

DOI: 10.3233/JAD-2007-11114

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 117-125, 2007

Authors: Strobel, Gabrielle

Article Type: Other

DOI: 10.3233/JAD-2007-11115

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 127-129, 2007

Authors: Strobel, Gabrielle

Article Type: Other

DOI: 10.3233/JAD-2007-11116

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 131-133, 2007

Article Type: Announcement

DOI: 10.3233/JAD-2007-11117

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 135-137, 2007

Article Type: Correction

DOI: 10.3233/JAD-2007-11118

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 139-139, 2007