Journal of Alzheimer's Disease - Volume 19, issue 4

Authors: Michel, Tanja Maria | Gsell, Wieland | Käsbauer, Ludwig | Tatschner, Thomas | Sheldrick, Abigail Jane | Neuner, Irene | Schneider, Frank | Grünblatt, Edna | Riederer, Peter

Article Type: Research Article

Abstract: For decades, it has been acknowledged that oxidative stress due to free radical species contributes to the pathophysiology of aging and neurodegenerative diseases. Aldehyde dehydrogenases (ALDH) not only transform aldehydes to acids but also act as antioxidant enzymes. However, little is known about the implications of the enzymatic family of ALDH in the context of neurodegenerative processes such as Alzheimer's disease (AD). We therefore examined the enzymatic activity of the mitochondrial ALDH-isoform in different regions of the postmortem brain tissue isolated from patients with AD and controls. We found that the mitochondrial ALDH activity was significantly increased only in the …putamen of patients suffering from AD compared to controls. This is of particular interest since mediators of oxidative stress, such as iron, are increased in the putamen of patients with AD. This study adds to the body of evidence that suggests that oxidative stress as well as aldehyde toxicity play a role in AD. Show more

Keywords: Aging, aldehydehydrogenase, Alzheimer's disease, dementia, free radicals, mitochondria, oxidative stress

DOI: 10.3233/JAD-2010-1326

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1295-1301, 2010

Authors: del Valle, Jaume | Duran-Vilaregut, Joaquim | Manich, Gemma | Casadesús, Gemma | Smith, Mark A. | Camins, Antoni | Pallàs, Mercè | Pelegrí, Carme | Vilaplana, Jordi

Article Type: Research Article

Abstract: Late-onset Alzheimer's disease (AD) is the most common form of AD appearing after 65 years of age. To date, however, there are no non-genetically manipulated rodent models that develop a similar sporadic onset of AD with age-related amyloid-β (Aβ) deposition. Although the senescence accelerated mouse prone 8 (SAMP8) mice have been proposed as a model of AD, the presence of Aβ deposits remains controversial. In this study, we describe the time course of Aβ deposition in SAMP8 mice as well as in control SAMR1 and ICR-CD1 strains of mice. From as early as 6 months onward, SAMP8 mice show Aβ …deposition in the hippocampus that increase in number and extent with age. These deposits are comprised of by clustered granules that contain Aβ42 , Aβ40 , and other Aβ protein precursor fragments. By marked contrast, control mice show only low numbers of Aβ clusters that do not develop until 15 months of age. The demonstration that SAMP8 mice present with amyloid deposits in their hippocampus makes this animal model a useful tool to understand the mechanisms involved in Aβ deposition in AD. Show more

Keywords: Aβ40, Aβ42, AβPP, aging, Alzheimer's disease, amyloid-β, hippocampus, SAMP8, SAMR1, senescence

DOI: 10.3233/JAD-2010-1321

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1303-1315, 2010

Authors: Cantoni, Claudia | Fenoglio, Chiara | Cortini, Francesca | Venturelli, Eliana | Villa, Chiara | Clerici, Francesca | Marcone, Alessandra | Benussi, Luisa | Ghidoni, Roberta | Gallone, Salvatore | Scalabrini, Diego | Franceschi, Massimo | Cappa, Stefano | Binetti, Giuliano | Mariani, Claudio | Rainero, Innocenzo | Giordana, Maria Teresa | Bresolin, Nereo | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: Two hundred and fifty one Italian patients with sporadic frontotemporal lobar degeneration (FTLD) and 259 age-matched controls were tested for association with the tagging single nucleotide polymorphisms (SNPs) rs741810 and rs1052352 in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS). Only patients negative for GRN mutations were included. Considering each SNP alone, no differences in either allelic or genotypic frequencies between patients and controls were found (P > 0.05), even stratifying according to gender or the presence of concomitant motor neuron disease. Haplotype analysis failed to detect haplotypes associated with FTLD. According to these results, FUS/TLS is not a susceptibility …factor for the development of sporadic FTLD. Show more

Keywords: Frontotemporal lobar degeneration (FTLD), fused in sarcoma/translated in liposarcoma (FUS/TLS), polymorphism, risk factor, variability

DOI: 10.3233/JAD-2010-1328

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1317-1322, 2010

Authors: Innocenti, Massimo | Salvietti, Emanuele | Guidotti, Martina | Casini, Angela | Bellandi, Silvano | Foresti, Maria Luisa | Gabbiani, Chiara | Pozzi, Andrea | Zatta, Paolo | Messori, Luigi

Article Type: Research Article

Abstract: Formation of amyloid-β (Aβ)1–42 amyloid fibrils, a characteristic feature of Alzheimer's disease (AD), was monitored in situ through atomic force microscopy (AFM). Well-structured amyloid fibrils slowly formed in solution within 24 hours for which high quality AFM pictures could be obtained. Remarkably, addition of either copper(II) or zinc(II) ions to the incubation medium, even at extremely low molar ratios, dramatically changed the Aβ1–42 aggregation profile and prevented fibril formation. Aggregates of different morphology appeared in accordance with previous observations: small globular aggregates upon addition of zinc; ill-structured micro-aggregates in the case of copper. The implications of these AFM …results are discussed in the context of current concepts for AD metallobiology. Show more

Keywords: Alzheimer's disease, amyloid-β, atomic force microscopy, metal ions

DOI: 10.3233/JAD-2010-1338

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1323-1329, 2010

Authors: Bowman, Gene L. | Shannon, Jackilen | Frei, Balz | Kaye, Jeffrey A. | Quinn, Joseph F.

Article Type: Research Article

Abstract: Oxidative damage is a consistent finding in a number of central nervous system (CNS) disorders. Uric acid (UA) is a potent hydrophilic antioxidant that is modified by diet and drug. Several lines of evidence suggest that plasma UA may modulate outcomes in neurologic disease, but little attention has been paid to CNS levels of UA. Our objective was to test the hypothesis that cerebrospinal fluid (CSF) UA is determined by plasma UA, modified by blood-brain barrier (BBB) integrity and associated with rate of cognitive decline in Alzheimer's disease (AD). Also, since UA and ascorbic acid may act as antioxidants for …one another, we also explored a potential interaction between them in the brain. Thirty-two patients with mild to moderate AD (Mini-Mental Status Exam 19 ± 5) participated in a longitudinal biomarker study for one year involving standardized clinical assessments. CSF and blood were collected at baseline for UA, ascorbic acid, and albumin. Cognitive measures were collected at baseline and again one year later. CSF UA was independent of age, gender, and AD severity. CSF and plasma UA were positively correlated (r = 0.669, p = 0.001) and BBB impairment was associated with higher CSF levels of UA (p = 0.028). Neither plasma nor CSF UA reached significant association with rates of cognitive decline over 1 year. CSF UA and CSF ascorbic acid were positively correlated (r = 0.388, p = 0.001). The hypothesis that CSF UA is determined by plasma UA and BBB integrity is supported, as is the hypothesis that UA and ascorbic acid are associated in CSF but not plasma. Adequately powered prospective studies would help assess any role for UA in primary and secondary prevention of AD. Show more

Keywords: Alzheimer's disease, ascorbic acid, blood-brain barrier, cerebrospinal fluid, uric acid

DOI: 10.3233/JAD-2010-1330

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1331-1336, 2010

Authors: Spitsin, Sergei | Koprowski, Hilary

Article Type: Article Commentary

DOI: 10.3233/JAD-2010-1336

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1337-1338, 2010

Authors: Doehner, Jana | Madhusudan, Amrita | Konietzko, Uwe | Fritschy, Jean-Marc | Knuesel, Irene

Article Type: Research Article

Abstract: Reelin is a large extracellular glycoprotein required for proper neuronal positioning during development. In the adult brain, Reelin plays a crucial modulatory role in the induction of synaptic plasticity and successful formation of long-term memory. Recently, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). We previously reported that aging in several species is characterized by a decline in Reelin-expressing interneurons and concomitant accumulation in amyloid-like plaques in the hippocampal formation, significantly correlating with cognitive impairments. In transgenic AD mice, we detected Reelin in oligomeric amyloid-β aggregates and in tight association with …fibrillary plaques. Here, we used immunohistochemistry at the light and electron microscopy level to characterize further the morphology, temporal and spatial progression, as well as the potential of Reelin-positive plaques to sequester murine amyloid-β peptides in wild-type mice. We developed a new immunohistochemical protocol involving a stringent protease pretreatment which markedly enhanced Reelin-immunoreactivity and allowed specific detection of variable shapes of murine anti-amyloid-β protein precursor-immunoreactivity in plaques in the hippocampus, likely representing N-terminal fragments and amyloid-β species. Ultrastructural investigations confirmed the presence of Reelin in extracellular space, somata of interneurons in young and aged wild-type mice. In aged mice, Reelin- and amyloid-β-immunoreactivity was detected in extracellular, spherical deposits, likely representing small intermediates or fragments of amyloid fibrils. Our results suggest that Reelin itself aggregates into abnormal oligomeric or protofibrillary deposits during aging, potentially creating a precursor condition for fibrillary amyloid-β plaque formation. Show more

Keywords: Amyloid-β plaques, AβPP, electron microscopy, hippocampus, immunohistochemistry, Mus musculus, non-transgenic, pepsin treatment, pre-fibrillary oligomers, sporadic Alzheimer's disease, stratum lacunosum-moleculare, ultrastructure

DOI: 10.3233/JAD-2010-1333

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1339-1357, 2010

Authors: Guo, Jian-Ping | Yu, Sheng | McGeer, Patrick L.

Article Type: Research Article

Abstract: Compounds that will inhibit buildup of amyloid-β(Aβ) deposits in Alzheimer's disease (AD) brain are potential therapeutic agents. Here we report the development of two simple in vitro screening assays to identify such agents. We use these assays to evaluate the relative potency of some possible candidates. One assay is based on binding of fluorescence-tagged Aβ1–42 to synthetic Aβ1–42 plated in wells of fluorescent black-wall microplates. Fluorescence-tagged Aβ1–42 solutions with and without blockers are then added to the plates, and the amount of bound fluorescence is measured. Another is a tissue type assay, where sections of unfixed AD …or AD model transgenic mouse brains are mounted on glass slides. The same solutions assayed in the microplate test are then added to tissue sections. Binding of fluorescence-tagged Aβ1–42 to the Aβ deposits in AD or transgenic brain tissue is detected with a fluorescence microscope. Good agreement is obtained between the two methods. Most of the tested agents have too low an affinity for Aβ1–42 to be effective clinically. Agents that may have marginal affinity according to these tests include 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (PGG), S-diclofenac, epigallocatechin gallate (EGCG), resveratrol, and extracts of spirulina, ginger, rhubarb, cinnamon, blueberries, and turmeric. Compounds which failed to show binding include scyllo-inositol, myo-inositol, rhamnose, ginkgolide A, emodin, rhein, caryophellene, curcumin, valproic acid, tramiprosate, and garlic extract. Show more

Keywords: Blueberry, cinnamon, Congo red, epigallocatechin gallate, garlic, ginger, resveratrol, rhubarb, spirulina, S-diclofenac, senile plaques, turmeric

DOI: 10.3233/JAD-2010-1331

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1359-1370, 2010

Authors: Kim, Insub | Lee, Junhee | Hong, Hyun Joo | Jung, Eun Sun | Ku, Yun Hyi | Jeong, In Kyong | Cho, Young Min | So, Insuk | Park, Kyong Soo | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Increasing evidence suggests that type 2 diabetes mellitus (T2DM) is strongly correlated with Alzheimer's disease (AD). To examine the relationship between T2DM and AD, autoantibodies against amyloid-Aβ were measured in the serum of T2DM patients and age-matched controls. Levels of Aβ autoantibody were measured by ELISA in serum samples of T2DM patients (n = 92) and age-matched control group (n = 106). Aβ autoantibody levels were increased in T2DM compared with age-matched controls by 45.4 ± 8.1% (p < 0.001). Females had higher Aβ autoantibody levels than males in both T2DM and control group. Aβ autoantibody levels in the T2DM …group were positively correlated with the levels of cholesterol (p = 0.011), low density lipoprotein cholesterol (p = 0.020), and triglycerides (p = 0.039). In conclusion, the level of Aβ autoantibody is dramatically elevated in patient serum of T2DM, and, as such, might be used as a possible biomarker for T2DM. Show more

Keywords: Aβ autoantibody, Alzheimer's disease, biomarker, cholesterol, type 2 diabetes mellitus

DOI: 10.3233/JAD-2010-1332

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1371-1376, 2010

Authors: Yenjerla, Mythili | LaPointe, Nichole E. | Lopus, Manu | Cox, Corey | Jordan, Mary Ann | Feinstein, Stuart C. | Wilson, Leslie

Article Type: Research Article

Abstract: NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) is a neuroprotective peptide that shows cognitive protection in patients with amnestic mild cognitive impairment, a precursor to Alzheimer's disease. NAP exhibits potent neuroprotective properties in several in vivo and cellular models of neural injury. While NAP has been found in many studies to affect microtubule assembly and/or stability in neuronal and glial cells at fM concentrations, it has remained unclear whether NAP acts directly or indirectly on tubulin or microtubules. We analyzed the effects of NAP (1 fM-1 μM) on the assembly of reconstituted bovine brain microtubules in vitro and found that it did not significantly (p …< 0.05) alter polymerization of either purified tubulin or of a mixture of tubulin and unfractionated microtubule-associated proteins. NAP also had no significant effect (p < 0.05) on the growing and shortening dynamics of steady-state microtubules at their plus ends, nor did it alter the polymerization or dynamics of microtubules assembled in the presence of 3-repeat or 4-repeat tau. Thus, the neuroprotective activity of NAP does not appear to involve a direct action on the polymerization or dynamics of purified tubulin or microtubules. Show more

Keywords: Microtubule dynamics, NAP, tau, tubulin polymerization

DOI: 10.3233/JAD-2010-1335

Citation: Journal of Alzheimer's Disease, vol. 19, no. 4, pp. 1377-1386, 2010