Journal of Alzheimer's Disease - Volume 14, issue 3

Authors: Zambrano, Ángara | Solis, Loretto | Salvadores, Natalia | Cortés, Marcos | Lerchundi, Rodrigo | Otth, Carola

Article Type: Research Article

Abstract: Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) belong to the family Herpesviridae, the subfamily Alphaherpesvirinae, and the genus Simplexvirus. They are ubiquitous, neurotropic, and the most common pathogenic cause of sporadic acute encephalitis in humans. Herpes simplex encephalitis (HSE) is associated with a high mortality rate and significant neurological, neuropsychological, and neurobehavioral sequelae, which afflict patients for life. HSV-1 has been suggested as an environmental risk factor for Alzheimer's disease. However, the mechanisms involved in HSV-1 infection that may trigger the neurodegenerative process are still unknown. In general, HSV-1 induced cytoskeletal alterations reported to …date involve the overall disruption of one or more elements of the cytoskeleton in cell lines. Axonal injury has recently attracted attention as a key predictor for the outcome of a number of brain disorders. Here we show that infection of mice neuronal cultures with HSV-1 result in marked neurite damage and neuronal death. Furthermore, in this in vitro model of infection, neurons manifested considerable alterations in microtubule dynamics and tau hyperphosphorylation. These results suggest a possible link between HSV-1 infection and neuronal cytoskeletal disruption. Show more

Keywords: Alzheimer's disease, HSE, HSV-1, neurodegeneration, tau

DOI: 10.3233/JAD-2008-14301

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 259-269, 2008

Authors: Ji, Chao | Aisa, Haji Akber | Yang, Nan | Li, Qing | Wang, Tao | Zhang, Ling | Qu, Kai | Zhu, Hai-Bo | Zuo, Ping-Ping

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is considered to be responsible for the pathogenesis of Alzheimer's disease. In the present study, the protective effect of Gossypium herbaceam extracts (GHE) on learning and memory impairment induced by Aβ were examined in vivo using Morris water maze and step through task. Furthermore, the antioxidant activity and neuroprotective effect of GHE was investigated with methods of histochemistry and biochemistry. These data showed that oral administration with GHE at the doses of 35, 70 and 140 mg/kg exerted an improved effect on the learning and memory impairment in rats induced by intracerebroventricular (i.c.v.) injection of 10 μg of …Aβ25–35 . Subsequently, the GHE afforded a beneficial action on promotion on the activity of glutathione peroxidase and catalase, as well as inhibition on the NF-κB activation in the hippocampus followed by the presence of Aβ25–35 . Meanwhile, the number of degenerating neurons with an apoptotic feature was dramatically decreased in hippocampus after treatment with GHE, implicating that its antioxidant stress and inhibition of NF-κB activation could be involved in the mechanism underlying neuroprotection of GHE against Aβ-induced cell death. These findings suggested that GHE might be a potential agent for treatment of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β, antioxidant stress, apoptosis, Gossypium herbaceam, NF-κB

DOI: 10.3233/JAD-2008-14302

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 271-283, 2008

Authors: Moretti, Davide Vito | Frisoni, Giovanni Battista | Pievani, Michela | Rosini, Sandra | Geroldi, Cristina | Binetti, Giuliano | Rossini, Paolo Maria

Article Type: Research Article

Abstract: The working hypothesis of paper is that the functional coupling of brain areas is combined with different neuroradiological substrates and has different clinical manifestations. 31 normal old subjects and 85 subjects with mild cognitive impairment (MCI) underwent EEG recordings and magnetic resonance imaging (MRI). Intrahemispheric and interhemispheric linear EEG coherences were computed. At first, all normal old and MCI subjects were compared. Subsequently, three subgroups of MCI were obtained based on neuroradiological substrate (subcortical cerebrovascular damage, MCI-CVD; cholinergic pathways vascular damage MCI-CHOL; and hippocampal atrophy, MCI-HIPP) and compared with a normal old sample matched for age, education and Mini-Mental State …Examination score. The group of MCI subjects compared to normal old subjects shows: 1) decrease of intrahemispheric coherence in fronto-parietal regions (both right and left hemisphere); 2) increase of interhemispheric coherence on frontal regions in delta frequency; and 3) increase of interhemispheric coherence on temporal regions (from delta to alpha3 frequency bands). In the MCI subgroups, hippocampal atrophy is linked to an increase of interhemispheric coherence seen on frontal and temporal regions whereas subcortical CVD is linked to the largest decrease of coherence in fronto-parietal regions. MCI-CVD patients performed worst on Trail Making Test battery whereas MCI-HIPP patients were impaired on Rey word list delayed recall and Rey figure recall. Show more

Keywords: Brain rhythms, cognitive tests, electroencephalography, linear coherence, mild cognitive impairment

DOI: 10.3233/JAD-2008-14303

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 285-299, 2008

Authors: Irizarry, Michael C. | Webb, David J. | Bains, Chanchal | Barrett, Steven J. | Lai, Robert Y. | Laroche, Janette P. | Hosford, David | Maher-Edwards, Gareth | Weil, John G.

Article Type: Research Article

Abstract: One limitation of several recent 24 week Alzheimer's disease (AD) clinical trials was the lack of cognitive decline detected by the AD Assessment Scale-cognitive subscale (ADAS-cog) in the placebo groups, possibly obscuring true medication effects. Data from 733 individuals in the placebo arms of six AD clinical trials performed 1996–1997 were pooled to examine the relationship of clinical, demographic, and genetic characteristics with the 24 week change in ADAS-cog. Baseline cognitive and functional status and the screening-to-baseline change in ADAS-cog were the strongest independent predictors of the 24 week change in ADAS-cog. The ADAS-cog did not detect progression in patients …with mild dementia (screening Mini-Mental State Exam, MMSE, ⩾20). The change in ADAS-cog from screening to baseline was inversely correlated with the 24 week change score; it was more difficult to detect cognitive decline at 24 weeks if individuals markedly worsened from screening to baseline. The effects of baseline MMSE and screening-to-baseline change in ADAS-cog generalized to the placebo group (N=106) of another AD study performed in 2004–2005. Overcoming lack of placebo decline in AD clinical trials will require scales more sensitive to cognitive decline in mild AD and strategies to reduce within-person variability in outcome measures. Show more

Keywords: ADAS-cog, Alzheimer's disease, clinical trials, MMSE, rosiglitazone

DOI: 10.3233/JAD-2008-14304

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 301-311, 2008

Authors: Agarwal, Smriti | Tannenberg, Rudi K. | Dodd, Peter R.

Article Type: Research Article

Abstract: Excitotoxicity may contribute to neuronal and synaptic loss in Alzheimer's disease (AD). Aberrant levels of gephyrin, a post-synaptic receptor-stabilizing protein, could affect the inhibitory modulation of excitatory impulses. We assayed gephyrin protein in two brain areas susceptible to neuronal loss in AD, and in a spared area, in autopsy tissue from normal subjects (n=15) and AD patients (n=5). Quantification was by in-gel immunodetection against known concentrations of a recombinant truncated gephyrin standard. Gephyrin abundance was significantly reduced (P < 0.01) in AD. Area-wise analysis showed that gephyrin levels were reduced in both spared and susceptible regions, indicating a global phenomenon. …When samples were categorized on an index of pathological severity, gephyrin levels decreased with increasing severity until a moderate index was reached, and then increased, suggesting that higher gephyrin levels might compensate for excitotoxic damage in late stages of the disease. AD males showed a more pronounced reduction in gephyrin levels than AD females cf same-sex controls. A major splice variant of gephyrin was detected in all cases and in all three brain areas. This is the first study of gephyrin expression in AD. Show more

Keywords: Excitotoxicity, human brain, inhibitory neurotransmission, pathogenesis, post-synaptic scaffold, protein expression, protein quantification, synaptic remodeling

DOI: 10.3233/JAD-2008-14305

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 313-321, 2008

Authors: Tchantchou, Flaubert | Graves, Michael | Falcone, Deane | Shea, Thomas B.

Article Type: Research Article

Abstract: When maintained on a folate-deficient, iron-rich diet, transgenic mice lacking in apolipoprotein E (ApoE–/– mice) demonstrate impaired activity of glutathione S-transferase (GST), resulting in increased oxidative species within brain tissue despite abnormally high levels of glutathione. These mice also exhibit reduced levels of S-adenosyl methionine (SAM) and increased levels of its hydrolysis product S-adenosyl homocysteine, which inhibits SAM usage. Supplementation of the above diet with SAM restored GST activity and eliminated reactive oxygen species at the expense of stockpiled glutathione, suggesting that one or more SAM-dependent reactions were required to maintain GST activity. We examined herein the impact of SAM …on GST activity using a cell-free assay. SAM stimulated GST activity in a dose-response manner when added to homogenates derived from the above ApoE–/– mice. SAM also increased activity of purified rat liver GST and recombinant GST. Filtering of SAM through a 4kDa cutoff and systematic withholding of reaction components eliminated the possibility of any additional contaminating enzyme. These findings confirm that SAM can exert a direct effect on GST activity. Since Alzheimer's disease is accompanied by reduced GST activity, diminished SAM and increased SAH, these findings underscore the critical role of SAM in maintenance of neuronal health. Show more

Keywords: Alzheimer's disease, apolipoprotein E, glutathione, methylation, oxidative stress, S-adenosyl methionine

DOI: 10.3233/JAD-2008-14306

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 323-328, 2008

Authors: Fernández, Jorge A. | Rojo, Leonel | Kuljis, Rodrigo O. | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Virtually none of the hypotheses on Alzheimer's disease (AD) pathogenesis address the earliest events that trigger the molecular alterations that precede cerebral degeneration and account for the diversity of risk factors that converge on a well-defined disease phenotype. We propose that long-term activation of the innate immune system by an individual array of risk factors constitutes a unifying mechanism leading to the triggering of an inflammatory cascade that converges in cytoskeletal alterations (tau aggregation, paired helical filament formation) as a previously hypothesized final common pathway in AD. The key pathogenic phenomena consist in the long-term, maladaptive activation of innate immunity-triggering …receptors – such as the toll-like and advanced glycation end-products receptors, and others located in the microglial membrane – by seemingly heterogeneous risk factors such as hyperlipidemia, hyperglycemia, oxidative stress, head injury, amyloid oligomers, etc. Our hypothesis provides a unifying mechanism that explains both the diversity of risk factors acting over long periods of time and the individual response to such insults. This formulation is amenable to both empirical testing and implementation into therapeutic strategies that may lead to effective prevention of AD as well as other disorders in which impaired regulation of the innate immunity is the unifying cause of the condition. Show more

Keywords: Alzheimer's disease, danger signals, glial cells, inflamatory cascades, innate immunity, neuronal cells, tau protein

DOI: 10.3233/JAD-2008-14307

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 329-333, 2008

Authors: Seripa, Davide | Matera, Maria Giovanna | Franceschi, Marilisa | Daniele, Antonio | Bizzarro, Alessandra | Rinaldi, Monica | Panza, Francesco | Fazio, Vito Michele | Gravina, Carolina | D'Onofrio, Grazia | Solfrizzi, Vincenzo | Masullo, Carlo | Pilotto, Alberto

Article Type: Research Article

Abstract: Reelin, a serine protease encoded by the RELN gene, is part of the apolipoprotein E (apoE) biochemical pathway that is involved in the pathogenesis of Alzheimer's disease (AD). Sex-related differences in the epidemiology, pathology and clinical characteristics of AD have been reported. To explore the potential contribution of RELN gene variants in the pathogenesis of AD, we investigated three polymorphisms spanning the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the splice-junction of exon 6 and in the coding region of exon 50. The analysis was made in …223 sporadic AD patients and 181 age-matched controls of Caucasian ethnicity. Significant differences between AD patients and controls were found in distribution of 5'UTR and rs607755 genotypes, whereas no differences were found in the distribution of rs2229874 genotypes. When patients and controls were divided according to sex, significant differences in genotype distribution were found in females and not in males, also after adjustment for APOE genotypes. These findings suggest that RELN gene variants may play a role in the pathogenesis of AD, particularly in females. Show more

Keywords: Alzheimer's disease, apolipoprotein E, case-control studies, gene polymorphism, Reelin, RELN, risk factors, single-nucleotide polymorphism

DOI: 10.3233/JAD-2008-14308

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 335-344, 2008

Authors: Hashioka, Sadayuki | Miklossy, Judith | Schwab, Claudia | Klegeris, Andis | McGeer, Patrick L.

Article Type: Research Article

Abstract: Microglial phagocytosis of amyloid-β (Aβ) deposits is involved in Aβ clearance in vivo. To explore the ability of microglia to phagocytose β, we cultured human microglia or human monocytic THP-1 cells directly on unfixed frontal cortex sections of an Alzheimer disease (AD) case. We found that when these cells were activated by lipopolysaccharide (LPS) plus interferon (IFN)-γ, they developed ameboid morphology and formed clusters around and attaching to amyloid plaques in the tissue. Some cells adhering to these plaques internalized Aβ and some appeared to be degraded. Nevertheless, no significant reduction of the overall Aβ burden was observed. If the …cells were not stimulated, they adhered poorly to the sections. We quantified THP-1 cell adhesion to an AD brain section compared with a normal brain section and found it to be significantly increased. If a brain section was rinsed with phosphate buffered saline containing 0.1% Triton X-100, most LPS/IFN-γ-activated THP-1 cells failed to adhere. However, in co-culture with human astrocytes, the number of adherent THP-1 cells was significantly increased. These results suggest that human microglial cells are capable of adhering to and phagocytosing post mortem AD plaque material but activation may be necessary. Astrocytes may further enhance the process. Show more

Keywords: Amyloid-β, amyloid-β clearance, astrocytes, microglia, microglial activation, phagocytosis, THP-1 cells

DOI: 10.3233/JAD-2008-14309

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 345-352, 2008

Authors: de la Torre, Jack C.

Article Type: Review Article

Abstract: Cardiovascular and cerebrovascular disease are reported to be major risk factors to Alzheimer's disease (AD). These risk factors mainly affect the elderly (over age 60) and previously were believed to only promote vascular dementia (VaD). Cardiovascular and cerebrovascular pathology involving structural lesions of the heart and carotid or vertebral artery stenosis stemming from intima media thickening or vessel plaque formation can insidiously reduce blood flow to the brain. Since heart and carotid artery disease are common findings in eldery patients and can provoke chronic cerebral hypoperfusion, we submit that individuals with even very mild memory complaints should undergo screening using …echocardiography and carotid Doppler ultrasound. These non-invasive, safe, cost-effective ultrasound techniques can often detect correctable or treatable early lesions involving the carotid arteries and the heart that contribute to cerebral hypoperfusion. Inasmuch as cerebral hypoperfusion can be a pathophysiologic trigger of AD, its prevention or attenuation should tangibly reverse or at least delay the onset and impact of severe cognitive meltdown. This clinical approach may have an important impact in reducing the number of new AD and VaD cases and lessen the catastrophic socio-economic burden these dementias are expected to have on the US healthcare system in the near future. Show more

Keywords: Aging, Alzheimer's disease, carotid Doppler ultrasound, cerebral blood flow, cerebral hypoperfusion, dementia, echocardiography, intima media thickness

DOI: 10.3233/JAD-2008-14310

Citation: Journal of Alzheimer's Disease, vol. 14, no. 3, pp. 353-359, 2008