Journal of Alzheimer's Disease - Volume 17, issue 2

Authors: Ryan, J. Michael | Grundman, Michael

Article Type: Letter

DOI: 10.3233/JAD-2009-1118

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 243-243, 2009

Authors: Bennett, Stuart | Grant, Melissa M. | Aldred, Sarah

Article Type: Review Article

Abstract: Alzheimer's disease and vascular dementia are the two most common types of dementia with the former being the most predominant. It is evident that oxidative stress, an environment where pro-oxidant species overwhelm antioxidant species, is involved in the pathogenesis of both forms of dementia. An increased level of reactive oxygen species in the vasculature, reduced nitric oxide bioavailability, and endothelial dysfunction leading to vascular disease is associated with vascular dementia. In Alzheimer's disease, an increased amount of amyloid-β peptide induces elevated reactive oxygen species production thereby causing neuronal cell death and damage. The recent observation that increased atherosclerotic plaque formation …is present in the main artery to the brain in Alzheimer's disease, coupled with the association of vascular risk factors with this disease, suggests a link between these two dementias. This review will argue that Alzheimer's disease and vascular dementia are two extremes of one disease, thus assuming a hypothesis where the clinical conditions referred to as dementia are part of a continuum. We propose that the majority of cases share a vascular pathology and that oxidative stress is central to this common pathology. Show more

Keywords: atherosclerosis, dementia, reactive oxygen species, vascular dysfunction

DOI: 10.3233/JAD-2009-1041

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 245-257, 2009

Authors: Larner, Andrew J. | Doran, Mark

Article Type: Review Article

Abstract: It is now more than ten years since pathogenic mutations were first described in the gene encoding presenilin 1 (PSEN1) on chromosome 14. Although PSEN1 mutations are “deterministic” for Alzheimer's disease, they are associated with marked heterogeneity in the clinical expression of neurological features. We review recent publications on the clinical neurological phenotype of PSEN1 mutations, many of which now appear only in abstracts or brief communications, perhaps because PSEN1 mutations are no longer regarded as “novel”. However, the clinical heterogeneity associated with these mutations prompts important questions about possible genetic and epigenetic factors which may modify disease phenotype. This …area, which may also be relevant to neurodegenerative disorders resulting from other genetic mutations, such as those in the tau gene, currently remains ill-understood. Show more

Keywords: Alzheimer's disease, presenilin 1

DOI: 10.3233/JAD-2009-1042

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 259-265, 2009

Authors: Erol, Adnan

Article Type: Review Article

Abstract: Peripheral insulin resistance is associated with hyperinsulinemia, which may be associated with brain insulin deficiency that is characteristic of sporadic Alzheimer's disease (sAD). Oxidative insult, which is the result of insulin associated disordered brain energy metabolism, is a significant early event in the pathological cascade of sAD. Aggregation of disease-specific proteins such as amyloid-β and tau may act as a compensatory response against the oxidative insult at the early periods. In the later stages, oxidative stress stimulates c-Jun N-terminal kinase (JNK) activation. The deficient insulin signaling is ultimately linked to protein kinase B (Akt) pathway and subsequently glycogen synthase kinase-3 …(GSK3) and forkhead transcription factors (FOXO). Peripheral insulin resistance related intense interactions between JNK, GSK3, FOXO factors, and p53, which may lead to apoptotic neuronal death, are outlined in a postulate. In light of this postulate, the importance of detailed knowledge of these common physiological processes for the opportunities of treatment that could prevent or reduce the onset of sAD is discussed as well. Show more

Keywords: Alzheimer's disease, FOXO, GSK3, insulin resistance, JNK, p53

DOI: 10.3233/JAD-2009-1047

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 267-276, 2009

Authors: Friedland, Robert P. | Petersen, Robert B. | Rubenstein, Richard

Article Type: Short Communication

Abstract: Dietary consumption of fish is widely recommended because of the beneficial effects of omega-3 polyunsaturated fatty acids on the risks of cardiovascular and Alzheimer's diseases. The American Heart Association currently recommends eating at least two servings of fish per week. We are concerned that consumption of farmed fish may provide a means of transmission of infectious prions from cows with bovine spongiform encephalopathy to humans, causing variant Creutzfeldt Jakob disease.

Keywords: Bovine spongiform encephalopathy (BSE), fish, prion, transmission

DOI: 10.3233/JAD-2009-1060

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 277-279, 2009

Authors: Kooistra, Joel | Milojevic, Julijana | Melacini, Giuseppe | Ortega, Joaquin

Article Type: Research Article

Abstract: Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the intermembrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in Alzheimer's disease (AD), which is characterized by the presence of aggregates of the amyloid-β peptide 1–42 (Aβ1-42 ). In this study, we analyzed the ability of HtrA2 to delay the aggregation of the model substrate citrate synthase (CS) and of the toxic Aβ1-42 peptide. We found that HtrA2 had a …moderate ability to delay the aggregation of CS in vitro, and this activity was significantly enhanced when the PDZ domain was removed suggesting an inhibitory role for this domain on the activity. Additionally, using electron microscopy and nuclear magnetic resonance analyses, we observed that HtrA2 significantly delayed the aggregation of the Aβ1-42 peptide. Interestingly, the protease activity of HtrA2 and its PDZ domain were not essential for the delay of Aβ1-42 peptide aggregation. These results indicate that besides its protease activity, HtrA2 also performs a chaperone function and suggest a role for HtrA2 in the metabolism of intracellular Aβ and in AD. Show more

Keywords: Alzheimer's disease, amyloid-β42, amyloid-β protein precursor, electron microscopy, HtrA2, nuclear magnetic resonance

DOI: 10.3233/JAD-2009-1037

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 281-294, 2009

Authors: Wang, Lili | Xu, Shengli | Xu, Xianhao | Chan, Piu

Article Type: Research Article

Abstract: As a natural product, (-)-Epigallocatechin-3-gallate (EGCG), has demonstrated remarkable neuronal protection by depressing oxidative stress in Parkinson's disease (PD). However, the molecular mechanisms underlying EGCG neuronal protection have not been clarified. Using 6-hydroxydopamine (6-OHDA)-treated human neuroblastoma SH-SY5Y cells as a PD cell model, we found that 6-OHDA can cause neuronal death by regulating the activity of STAT3. Pretreatment of SH-SY5Y cells with EGCG (0.1–10 μM) significantly attenuated the cell death induced by 6-OHDA. In addition, the STAT3 activity decline induced by 6-OHDA in SH-SY5Y cells can be completely prevented by the presence of 1 μM of EGCG, and neuronal cell …proliferation can be stimulated by EGCG treatment. These results clearly demonstrate that the disruption of STAT3 signaling by 6-OHDA makes significant contribution to the neuronal death in PD, and the protection of EGCG on neurons against oxidative stress-induced cell death may result from the re-stimulation of STAT3 signaling pathway. Our study not only clarified the role of STAT3 signaling pathway in oxidative stress-induced neuronal cell death, but also identified its involvement in the protection mechanism of EGCG on neurons in PD. The data resulting from our study also suggest that STAT3 may serve as a potential therapeutic target for the drug development in PD. Show more

Keywords: (-)-Epigallocatechin-3-gallate (EGCG), 6-Hydroxydopamine (6-OHDA), neuroprotection, Parkinson's disease, signal transducers and activators of transcription (STAT)

DOI: 10.3233/JAD-2009-1048

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 295-304, 2009

Authors: Bates, Kristyn A. | Sohrabi, Hamid R. | Rodrigues, Mark | Beilby, John | Dhaliwal, Satvinder S. | Taddei, Kevin | Criddle, Arthur | Wraith, Megan | Howard, Matthew | Martins, Georgia | Paton, Athena | Mehta, Pankaj | Foster, Jonathan K. | Martins, Ian J. | Lautenschlager, Nicola T. | Mastaglia, Frank L. | Laws, Simon M. | Gandy, Samuel E. | Martins, Ralph N.

Article Type: Research Article

Abstract: A strong link is indicated between cardiovascular disease (CVD) and risk for developing Alzheimer's disease (AD), which may be exacerbated by the major AD genetic risk factor apolipoprotein Eε4 (APOEε4). Since subjective memory complaint (SMC) may potentially be an early indicator for cognitive decline, we examined CVD risk factors in a cohort of SMC. As amyloid-ε (Aβ) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased LDL, reduced HDL, and increased body fat) would be associated with plasma Aβ levels. We explored this in 198 individuals with and without SMC (average age …= 63 years). Correlations between Aβ40 and HDL were observed, which were stronger in non-APOEε4 carriers (rho = −0.315, p < 0.001) and in SMC (rho = −0.322, p = 0.01). There was no relationship between percentage body fat and Aβ40 in this cohort. Age and HDL remained predictive for plasma Aβ40 using multivariate regression analysis. We report a novel negative association between HDL and Aβ, which if demonstrated to be causal has implications for the development of lifestyle interventions and/or novel therapeutics. The relationship between HDL and Aβ and the potential significance of such an association needs to be validated in a larger longitudinal study. Show more

Keywords: Aging, amyloid-β, apolipoprotein E, cholesterol, dementia, high density lipoprotein

DOI: 10.3233/JAD-2009-1050

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 305-318, 2009

Authors: Tortosa, Elena | Santa-Maria, Ismael | Moreno, Francisco | Lim, Filip | Perez, Mar | Avila, Jesús

Article Type: Research Article

Abstract: Tau pathology, associated with Alzheimer's disease, is characterized by the presence of phosphorylated and aggregated tau. Phosphorylation of tau takes place mainly in the vicinity of the tubulin-binding region of the molecule and its self aggregation is also mediated via this tubulin-binding region. Tau phosphorylation and aggregation have been related with conformational changes of the protein. These changes could be regulated by chaperones such as heat shock proteins, since one of these, heat shock protein 90 (Hsp90), has already been described as a putative tau-binding protein. In this work, we have confirmed the interaction of Hsp90 with tau protein and …report that binding of Hsp90 to tau facilitates a conformational change that could result in its phosphorylation by glycogen synthase kinase 3 and its aggregation into filamentous structures. Show more

Keywords: Aggregation, Hsp90, phosphorylation, tau

DOI: 10.3233/JAD-2009-1049

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 319-325, 2009

Authors: Dolga, Amalia M. | Granic, Ivica | Nijholt, Ingrid M. | Nyakas, Csaba | van der Zee, Eddy A. | Luiten, Paul G.M. | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Besides a beneficial cardiovascular effect, it was recently suggested that statins can also exert neuroprotective actions. In a previous study, we provided in vitro evidence that lovastatin treatment abates excitotoxic cell death in primary cortical neurons. Here, we investigated the neuroprotective effect of lovastatin in an in vivo mouse model. We found that administration of lovastatin (20 mg/kg) significantly protects cholinergic neurons and their cortical projections against N-methyl-D-aspartate (60 nmol)-induced cell death in the magnocellular nucleus basalis, a neuronal cell group that is characteristically affected in Alzheimer's disease. Furthermore, lovastatin-mediated neuroprotection was shown to be dependent on protein kinase B …(PKB)/Akt signaling since treatment with the PKB/Akt inhibitor LY294002 blocked the lovastatin-induced neuroprotective effect. The loss of cholinergic neurons after the lesion in the magnocellular nucleus basalis resulted in memory impairment as tested in a passive avoidance paradigm. This was reverted by pre-lesion lovastatin treatment. From these studies we conclude that treatment with lovastatin may provide protection against neuronal injury in excitotoxic conditions associated with neurodegenerative diseases including Alzheimer's disease. Show more

Keywords: Cholinergic neurons, excitotoxicity, lovastatin, magnocellular nucleus basalis, NMDA, passive avoidance test, PKB/Akt

DOI: 10.3233/JAD-2009-1052

Citation: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 327-336, 2009