Journal of Alzheimer's Disease - Volume 13, issue 1

Authors: Banwait, Surita | Galvan, Veronica | Zhang, Junli | Gorostiza, Olivia F. | Ataie, Marina | Huang, Wei | Crippen, Danielle | Koo, Edward H. | Bredesen, Dale E.

Article Type: Research Article

Abstract: In addition to the proteolytic cleavages that give rise to amyloid-β (Aβ), the amyloid-β protein precursor (AβPP) is cleaved at Asp664 intracytoplasmically. This cleavage releases a cytotoxic peptide, APP-C31, removes AβPP-interaction motifs required for signaling and internalization, and is required for the generation of AD-like deficits in a mouse model of the disease. Although we and others had previously shown that Asp664 cleavage of AβPP is increased in AD brains, the distribution of the Asp664-cleaved forms of AβPP in non-diseased and AD brains at different ages had not been determined. Confirming previous reports, we found that Asp664-cleaved forms of AβPP …were increased in neuronal cytoplasm and nuclei in early-stage AD brains but were absent in age-matched, non-diseased control brains and in late-stage AD brains. Remarkably, however, Asp664-cleaved AβPP was prominent in neuronal somata and in processes in entorhinal cortex and hippocampus of non-diseased human brains at ages <45 years. Our observations suggest that Asp664 cleavage of AβPP may be part of the normal proteolytic processing of AβPP in young (<45 years) human brain and that this cleavage is down-regulated with normal aging, but is aberrantly increased and altered in location in early AD. Show more

Keywords: Alzheimer's disease, Amyloid-β protein precursor, APP-C31, APPNeo, Asp664, proteolytic processing

DOI: 10.3233/JAD-2008-13101

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 1-16, 2008

Authors: Guerreiro, Nelson | Staufenbiel, Matthias | Gomez-Mancilla, Baltazar

Article Type: Research Article

Abstract: Alzheimer's disease is the most prevalent form of dementia associated with aging in the human population for which there is no biomarker for accurate and effective diagnosis at its early stage or monitoring of disease progression. In this study, we used 2-D DIGE to identify Alzheimer's disease-related proteins in the brains of APP23 mice used as a model for studying cerebral amyloidosis. Protein expression profiles in the brain of 2- and 24-month old female transgenic mice, displaying pre-plaque and plaque phenotypes, respectively, and 24-month old wild-type mice were compared to identify if changes at the protein level could be implicated …in the early molecular events leading to cerebral amyloidosis. Seven such proteins were identified including kinesin heavy chain, dihydropyrimidinase related protein 2, β-tubulin, two isomers of 3-phosphoglycerate dehydrogenase, ubiquinol cytochrome c reductase, and heat shock protein 84. The dysregulation of these proteins may have implications on pathways such as the mitochondrial respiratory chain, axonal transport, axon guidance, L-Serine biosynthesis and cytoskeletal reorganization, and thereby may represent events that precede and participate in the formation of senile plaque. Other detected protein changes were observed only in the plaque phenotype, and so are likely to be a consequence of plaque deposition and/or associated with neurodegenerative/repair processes. These proteins provide a basis for further dissecting the early mechanisms of Alzheimer's disease, and exploring their implications as relevant biomarker candidates of incipient Alzheimer's disease and progression in man. Show more

Keywords: Alzheimer's disease, animal model, biomarker, proteomics, transgenics, 2-D DIGE

DOI: 10.3233/JAD-2008-13102

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 17-30, 2008

Authors: Wang, Wei | Shinto, Lynne | Connor, William E. | Quinn, Joseph F.

Article Type: Research Article

Abstract: Carotenoids are fat-soluble antioxidants that may protect polyunsaturated fatty acids, such as n-3 fatty acids from oxidation, and are potentially important for Alzheimer's disease (AD) prevention and treatment. Fasting plasma carotenoids were measured in 36 AD subjects and 10 control subjects by HPLC. Correlations between plasma carotenoid levels, red blood cell (RBC) n-3 fatty acids, and dementia severity were examined in AD patients. Moderately severe AD patients (MMSE=16–19) had much lower plasma levels of two major carotenoids: lutein and beta-carotene, compared to mild AD patients (MMSE=24–27) or controls. Among AD patients, variables (lutein, beta-carotene, RBC docosahexaenoic acid (DHA) and …LDL-cholesterol) were significantly correlated with MMSE. A lower MMSE score was associated with lower lutein, beta-carotene and RBC DHA levels, and a higher LDL-cholesterol level. These variables explained the majority of variation in dementia severity (55% of variance in MMSE). Lutein, beta-carotene and beta-cryptoxanthin were positively correlated with RBC DHA in AD patients. The association between higher carotenoids levels and DHA and higher MMSE scores, supports a protective role of both types of nutrients in AD. These findings suggest targeting multiple specific nutrients, lutein, beta-carotene, and DHA in strategies to slow the rate of cognitive decline. Show more

Keywords: Alzheimer's disease, beta-carotene, carotenoids, dementia, docosahexaenoic acid, lutein

DOI: 10.3233/JAD-2008-13103

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 31-38, 2008

Authors: Pomponi, Massimiliano | Bria, Pietro | Pomponi, Massimo

Article Type: Research Article

Abstract: Background:: In Alzheimer’s disease (AD), the common symptom is loss of memory. Learning and memory are associated with amoeboid movements of synaptic endings. Docosahexaenoic acid (DHA) is a major lipid constituent of synaptic end sites. Minor changes in the fluidity of phospholipidic membranes have a dramatic impact on the function of synapses, where membrane fluidity may influence the neurotransmitter receptor activity. Method:: Studies pertaining to the role of DHA as a neuroprotective agent was reviewed. Results:: Here we will show a conceptual framework for the role of DHA in the prevention of AD. The DHA content …has been shown to be decreased in the brain and plasma of patients affected by AD. Aspirin triggers the generation of DHA-derived mediators that are themselves neuroprotective. Conclusion:: Adequate dietary intakes of the neuroprotective DHA (and aspirin?) may slow down the progression of AD. An essential reserve of synapses from early development is needed. Show more

Keywords: Alzheimer's disease, aspirin, docosahexaenoic acid, neuroprotectin D1, PPARs

DOI: 10.3233/JAD-2008-13104

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 39-47, 2008

Authors: Pankhurst, Quentin | Hautot, Dimitri | Khan, Nadeem | Dobson, Jon

Article Type: Short Communication

Abstract: A study of the magnetic properties of superior temporal gyrus brain tissue from 11 Alzheimer's disease (AD) and 11 age-matched control subjects demonstrates an exponential correlation between the concentrations of the Fe2+ -ion-containing iron oxide, magnetite (Fe3 O4 ), and the fraction of those particles that are smaller than 20 nm in diameter. These data provide circumstantial evidence in favor of their genesis within the 8 nm diameter cores of the iron storage protein ferritin. We also show, for the first time, that the total concentration of biogenic magnetite is generally higher in the AD brain (in some cases as …much as 15 times greater than controls) and that there are gender-based differences, with AD female subjects having significantly higher concentrations than all other groups. These results provide insights which may guide current efforts to develop iron-based MRI diagnosis of AD. Show more

DOI: 10.3233/JAD-2008-13105

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 49-52, 2008

Authors: Wang, Deng-Shun | Uchikado, Hirotake | Bennett, David A. | Schneider, Julie A. | Mufson, Elliott J. | Wu, Joanne | Dickson, Dennis W.

Article Type: Research Article

Abstract: Background:: Protein cross-linking and aggregation are important molecular processes in Alzheimer’s disease (AD), and tissue transglutaminase (tTG) catalyzes protein cross-linking. Objectives:: To measure tTG, tTG enzyme activity and isopeptide, which is the product of tTG, in brain and to relate them to cognitive scores. Methods:: tTG and isopeptide levels were measured in frontal gray matter of 10 normal (NCI), 10 mild cognitive impairment (MCI) and 9 AD brains from the Religious Orders Study. tTG enzymatic activity was measured with a fluorescence assay. Results:: tTG protein and enzyme activity were highest in AD, but not …significantly greater than MCI or NCI. In contrast, isopeptide immunoreactivity in formic acid extracts was significantly greater in AD than NCI and MCI. The level of insoluble formic acid extractable isopeptide correlated with several measures of cognitive function, including word generation and perceptual speed. Multiple linear regression analyses indicated that insoluble isopeptide immunoreactivity could be accounted for by a combination of factors in the formic acid extract, including Aβ, ubiquitin and tau. Conclusions:: Accumulation of insoluble proteins with isopeptide bonds correlates with cognitive impairment. The relationship of isopeptide to other proteins that are also enriched in formic acid extracts suggests that several substrates of tTG may play a role in the pathogenesis of AD. Show more

Keywords: Amyloid, isopeptide, mental status, neuropsychology, tau, transglutaminase, ubiquitin

DOI: 10.3233/JAD-2008-13106

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 53-66, 2008

Authors: Shea, Thomas B. | Chan, Amy

Article Type: Short Communication

Abstract: Recent preclinical and clinical findings demonstrate that dietary supplementation with S-adenosyl methionine alleviates a variety of risk factors and hallmarks associated with Alzheimer's disease. These findings support and extend prior studies, some of which are decades old, and support the notion that nutritional supplementation may represent an important augmentation for therapy in Alzheimer's disease.

DOI: 10.3233/JAD-2008-13107

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 67-70, 2008

Authors: Brock, Brian | Basha, Riyaz | DiPalma, Katie | Anderson, Amy | Harry, G. Jean | Rice, Deborah C. | Maloney, Bryan | Lahiri, Debomoy K. | Zawia, Nasser H.

Article Type: Research Article

Abstract: Alzheimer's disease is characterized by amyloid-β peptide (Aβ)-loaded plaques in the brain. Aβ is a cleavage fragment of amyloid-β protein precursor (APP) and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 (SP1), which has been shown to be required for the regulation of APP and Aβ. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization of SP1, APP, and Aβ in various brain regions of rodent and primate models using immunohistochemistry. We observed …that overall distribution and cellular localization of SP1, APP, and Aβ are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Aβ in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. Show more

Keywords: Amyloid-β, amyloidogenesis, amyloid-β protein precursor, Brain, immunohistochemistry, monkey, SP1, transcription

DOI: 10.3233/JAD-2008-13108

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 71-80, 2008

Authors: Matrone, Carmela | Di Luzio, Anna | Meli, Giovanni | D'Aguanno, Simona | Severini, Cinzia | Ciotti, Maria Teresa | Cattaneo, Antonino | Calissano, Pietro

Article Type: Research Article

Abstract: Nerve growth factor (NGF) exerts a trophic, antiapoptotic action on several neuronal targets, including the clonal cell line PC12. In the current study, we demonstrate that withdrawal of this neurotrophin from PC12 differentiated cells causes overproduction of amyloid-β (Aβ) peptides, which are the most toxic protein fragments directly implicated in the development of Alzheimer disease (AD), concomitantly with cell death by apoptosis. Aβ production and apoptotic death, occurring after withdrawal from NGF-differentiated PC12 cells, are completely inhibited by β- and γ-secretase inhibitors and by antibodies directed against Aβ peptides, favouring maintenance of PC12 morphology and neuritic network. These peptides are …partially released and largely deposited as aggregates only soluble with strong detergent treatment generally employed to dissolve senile plaques. Furthermore, partial silencing of APP mRNA, by siRNA, reduces not only the extent of Aβ production but also apoptotic death. Aβ production and apoptosis are also induced in differentiated PC12 cells by kinase inhibitors of Trk-A, the high affinity receptor of NGF and, in this case, the co-incubation with β- and γ-secretase inhibitors totally revert apoptosis. Show more

Keywords: Alzheimer disease, amyloid-β, amyloid-β protein precursor, apoptosis, neurotrophin, NGF, NGF target neurons

DOI: 10.3233/JAD-2008-13109

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 81-96, 2008

Authors: Bakchine, S. | Loft, H.

Article Type: Research Article

Abstract: Memantine is a moderate affinity, uncompetitive NMDA receptor antagonist currently approved for the treatment of moderate to severe Alzheimer's disease (AD). A 24-week, double-blind, placebo-controlled, study (Study 99679) conducted in Europe evaluated the efficacy and tolerability of 20 mg/day memantine in patients with mild to moderate AD. Patients were randomised to either memantine or placebo in a 2:1 ratio. Efficacy was primarily assessed as change from baseline in ADAS-cog and CIBIC-plus score. Of 470 patients randomised and treated (memantine, n=318; placebo, n=152), 85% and 91% completed the study. Memantine-treated patients showed statistically significant improvement relative to placebo at weeks 12 …and 18, and numerical superiority at week 24 on both efficacy scales. The lack of significance at week 24 was attributed to an unexpectedly high placebo response. Memantine was well tolerated with an adverse event profile similar to placebo. The data presented support the efficacy of memantine in mild to moderate AD. Show more

Keywords: Memantine, Alzheimer's disease, mild to moderate, NMDA receptor

DOI: 10.3233/JAD-2008-13110

Citation: Journal of Alzheimer's Disease, vol. 13, no. 1, pp. 97-107, 2008