Journal of Alzheimer's Disease - Volume 24, issue s2

Authors: Britton, Gabriel B. | Smith, Mark A. | Perry, George | Sambamurti, Kumar | Jagannatha Rao, K.S.

Article Type: Editorial

DOI: 10.3233/JAD-2011-110021

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 1-2, 2011

Article Type: Introduction

DOI: 10.3233/JAD-2011-110022

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 3-4, 2011

Authors: Rammouz, Georges | Lecanu, Laurent | Aisen, Paul | Papadopoulos, Vassilios

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive, yet irreversible, neurodegenerative disease for which there are limited means for its ante-mortem diagnosis. We previously identified a brain- and cell-specific oxidative stress-mediated mechanism for dehydroepiandrosterone (DHEA) biosynthesis present in rat, bovine, and human brain, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and amyloid-β peptide. Using brain tissue specimens from control and AD patients we subsequently provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus …depleting the levels of the precursor present in the blood stream. Here, we tested for the presence of this DHEA precursor in human serum using a simple Fe2+ -based reaction and determined the amounts of DHEA formed. A total of 86 subjects were included in this study: 19 male and 20 female AD patients; 18 male and 22 female age-matched controls; and 4 men and 3 women with mild cognitive impairment. Serum oxidation resulted in a dramatic increase of DHEA level in control patients, whereas only a moderate or no increase was observed in the AD patients. The DHEA variation after oxidation correlated with the patients' cognitive and mental status. These results suggest that the comparison of DHEA levels in patient serum before and after oxidation could provide a useful tool to diagnose AD. Show more

Keywords: Alzheimer's disease, blood, DHEA, diagnosis, gas chromatography, mass spectrometry, mild cognitive impairment, oxidative stress

DOI: 10.3233/JAD-2011-101941

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 5-16, 2011

Authors: Pérez-González, Rocío | Antequera, Desiree | Vargas, Teo | Spuch, Carlos | Bolós, Marta | Carro, Eva

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile amyloid-β (Aβ) plaques, neuronal death, and cognitive decline. Neurogenesis in the adult hippocampus, which is notably affected by progressive neurodegeneration and Aβ pathology, is implicated in learning and memory regulation. Human postmortem brains of AD patients and AβPP/PS1 double transgenic mice show increased neurodegeneration. Leptin, an adipose-derived hormone, promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the AD brain is still unknown. Thus, we sought to determine if leptin stimulated the proliferation of neuronal precursors in AβPP/PS1 mice. We estimated the number …proliferating hippocampal cells after intracerebroventricular administration of a lentiviral vector encoding leptin. After 3 months of treatment with leptin we observed an increase in the number of BrdU-positive cells in the subgranular zone of the dentate gyrus, as shown by morphometric analysis. This increase resulted mainly from an increased proliferation of neuronal precursors. Additionally, leptin led to an attenuation of Aβ-induced neurodegeneration, as revealed by Fluoro-Jade staining. Our results suggest that in AβPP/PS1 mice, leptin exerts changes resembling acute neurotrophic and neuroprotective effects. These effects could serve as the basis for the design of future treatment strategies in AD. Show more

Keywords: Alzheimer's disease, amyloid-β, lentivirus, leptin, neurodegeneration, neurons

DOI: 10.3233/JAD-2011-102070

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 17-25, 2011

Authors: Matsuoka, Masaaki

Article Type: Review Article

Abstract: Despite a bulk of evidence supporting the idea that increased neurotoxic insults lead to Alzheimer's disease (AD), the possibility still remains that insufficiency of an endogenous defense system contributes to the disease progression. Humanin is a bioactive peptide that is likely to inhibit both neuronal death and dysfunction only related to AD by binding to a Humanin receptor on the cell-surface and by activating a STAT3-mediated signal, preventing the onset of dementia. A couple of recent studies presented evidence suggesting that the Humanin signal is decreased in neurons of AD patients. If this is the case, the restoration or activation …of the Humanin signal in neurons may change the course of AD. Show more

Keywords: Alzheimer's disease, Humanin, neuronal death, neuronal dysfunction

DOI: 10.3233/JAD-2011-102076

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 27-32, 2011

Authors: Yanagisawa, Daijiro | Taguchi, Hiroyasu | Yamamoto, Akitsugu | Shirai, Nobuaki | Hirao, Koichi | Tooyama, Ikuo

Article Type: Research Article

Abstract: Studies of Alzheimer's disease (AD) strongly support the hypothesis that amyloid-β (Aβ) deposition in the brain is the initiating event in the progression of AD. Aβ peptides easily form long insoluble amyloid fibrils, which accumulate in deposits known as senile plaques. On the other hand, recent work indicated that soluble Aβ oligomers, rather than monomers or insoluble Aβ fibrils, might be responsible for neuronal and synaptic dysfunction in AD. Curcumin, a low molecular weight yellow-orange pigment derived from the turmeric plant, has shown therapeutic effects in transgenic mouse models of AD. However, it remains unclear whether curcumin interacts directly with …the Aβ oligomers. This study investigated any interaction between curcumin and Aβ oligomers such as globulomer and Aβ-derived diffusible ligand (ADDL). Globulomer was observed as a cluster of spherical structures by electron microscopic analysis, and ADDL was also detected as small spherical structures. Fluorescence analysis revealed a significant increase in the fluorescence of curcumin when reacted with both oligomers. Furthermore quartz crystal microbalance analysis showed significant frequency decreases in oligomer-immobilized electrodes following the addition of curcumin. These results strongly suggested that curcumin binds to Aβ oligomers and to Aβ fibrils. The association of curcumin with Aβ oligomers may contribute to the therapeutic effect on AD. Based on these findings, curcumin could provide the basis of a novel concept in AD therapies targeting Aβ oligomers. Show more

Keywords: Alzheimer's disease, amyloid-β, curcumin, oligomers

DOI: 10.3233/JAD-2011-102100

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 33-42, 2011

Authors: Townsend, Matthew

Article Type: Review Article

Abstract: Alzheimer's disease (AD) continues to be one of most difficult human diseases to treat. The past 18 months have been a cruel reminder of the challenges of finding new and effective treatments. In 2010, several large Phase III clinical trials were terminated for lack of therapeutic efficacy. Concurrently, an NIH expert review panel was resigned to conclude that there was insufficient scientific evidence to recommend any treatment choices for slowing the progression of AD. Why has this disease proved so daunting? The answer is complex. To begin, it is still not clear whether AD is one disease with a single …cause or multiple syndromes with common symptoms and/or a common pathology. Resolving this question is a prerequisite for forecasting whether to expect a ‘magic bullet’ therapy or only incremental progress in select patient populations. This review will explore some of the details of recent clinical trials and consider some of the lessons learned. As therapies approach clinical trials, it is essential to understand the expectations of regulatory agencies such as the FDA and EMA to obtain approval. Lastly, we will cover some of the essential gaps in our scientific understanding about the disease process and the impact this has on target validation. The hope of finding of a quick cure for AD without a complete understanding of the disease may have been too optimistic. However, a prudent review of the scientific evidence, a clear understanding of the expectations of regulators, and careful attention to patient needs may still lead to good therapies in the foreseeable future. Show more

Keywords: Alzheimer's disease, amyloid, clinical trials, pharmaceuticals

DOI: 10.3233/JAD-2011-110020

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 43-52, 2011

Authors: Decourt, Boris | Sabbagh, Marwan N.

Article Type: Review Article

Abstract: The diagnosis of Alzheimer's disease (AD) relies principally on clinical criteria for probable and possible AD as defined by the NINCDS-ADRDRA. The field is desperately lacking of biological markers to assist with AD diagnosis and verification of treatment efficacy. According to the Consensus Report of the Working Group on Molecular and Biochemical Markers of Alzheimer's Disease, in order to qualify as a biomarker the sample in question must adhere to certain basic requirements, including the ability to: reflect AD pathology and differentiate it from other dementia with an 80% sensitivity; be reliable and reproducible; be easy to perform and analyze; …remain relatively inexpensive. Beta secretases are crucial enzymes in the pathogenesis of AD. Given its primary role in brain amyloidogenesis and its ubiquitous expression, one may consider measuring peripheral BACE1 levels and activity as biomarkers of AD, like performed in the brain and cerebrospinal fluid. However, very little is known about the periphery and whether peripheral BACE1 is involved in AD pathogenesis or mirrors AD progression. Moreover, no investigation has focused on the possibility of monitoring peripheral BACE1 to assess the efficiency of BACE1 inhibitors during the course of clinical trials. Part of the problem may be attributed to the lack of sensitive molecular tools which are absolutely necessary to use BACE1 as a biomarker. In this review we evaluate the progress and feasibility of developing BACE1 as a biomarker for AD in different tissues. Show more

Keywords: Alzheimer's disease, BACE1, β-secretase, biomarker, blood, brain, cerebrospinal fluid

DOI: 10.3233/JAD-2011-110017

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 53-59, 2011

Authors: Kurz, Alexander | Perneczky, Robert

Article Type: Review Article

Abstract: An imbalance between production and clearance of the amyloid-β peptide (Aβ) is a key momentum of the complex pathological cascade of Alzheimer's disease (AD). It is caused by overproduction of Aβ or, more frequently, by impaired clearance from brain. Clearance can be reduced by increased aggregation, defective degradation, disturbed balance of transport across the blood-brain barrier, or inefficient peripheral removal of the peptide. In recent years these mechanisms have become targets of pharmacological interventions. Although several compounds have been discarded on the grounds of limited clinical efficacy, all major clearance-related approaches still hold promise. Some drug candidates have advanced to …Phase III trials including anti-Aβ antibodies, metal complexing agents, ginseng extracts, and intravenous immunoglobulins. Data are currently not available from these studies that might allow an evaluation of efficacy and safety. Phase II trials on active and passive immunization have demonstrated a striking discrepancy between significant neurobiological effects regarding the removal of Aβ deposits and minor clinical outcomes. This does not preclude the possibility that clearance-related strategies have the potential of saving neurons and synapses via reducing the levels of soluble and particularly toxic Aβ species in brain. It may take longer than projected in ongoing trials for such neurobiological effects to translate into measurable changes of clinical progression. Show more

Keywords: Aggregation, Alzheimer's disease, amyloid-β, blood-brain barrier, clearance, degradation

DOI: 10.3233/JAD-2011-102139

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 61-73, 2011

Authors: Vincent, Bruno | Govitrapong, Piyarat

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is by far the main cause of dementia in the aged population. Because the amyloid-β peptide (Aβ) is the main component of senile plaques that develop in the brain of affected patients, numerous studies aimed at preventing its production or aggregation were conducted during the past 25 years. The inhibition of Aβ production via pharmacological inhibition of β- and γ-secretases is, with vaccination, one of the two main current challenges aimed at curing AD. However, the fact that there exist numerous substrates of these two activities renders this approach problematic since treatments with β- or γ-secretase inhibitors …can cause deleterious effects. An alternative to the inhibition of the amyloidogenic enzymes would be to activate the α-secretase processing of AβPP. This cleavage is performed by two members of the disintegrin family of metalloproteases (ADAM10 and ADAM17). It is noteworthy that this cleavage can be seen as doubly beneficial regarding AD since it both occurs in the middle of the Aβ sequence and triggers the release of the neuroprotective sAβPPα product. However, similarly to β- and γ-secretases, ADAM10 and ADAM17 are responsible for the cleavage of a large number of proteins, the processing of some of them being tightly associated with important physiological functions but also with severe pathologies. This review focuses on our current knowledge of the various natural or synthetic compounds able to trigger α-secretase activities and on the possible ways to circumvent the deleterious side effects that would result from their broad activation. Show more

Keywords: α-Secretase, AβPP, sAβPPα, Alzheimer's disease, amyloid peptide, disintegrins

DOI: 10.3233/JAD-2011-110218

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 75-94, 2011