Journal of Alzheimer's Disease - Volume 28, issue 1

Authors: Polidori, M. Cristina | Pientka, Ludger

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is slowly but steadily undergoing a profound reshaping of the definition and approach caused by the frustrating gap between poorly controlled AD epidemiology and repeated lack of success in finding a cure. The frequently reported and currently accepted role of vascular pathology and vascular risk factors in AD pathophysiology in recent years is one major aspect of this need for a severe adjustment in the modus operandi in AD. A clue into the importance that the interdependence between AD and vascularity has gained in scientific opinion is the large amount of recent reviews, almost reaching that of …original papers, on the topic. Far from aiming to meta-analyze all in vitro, in vivo, and ex vivo experiments, animal model research, clinical investigations, and epidemiological surveys conducted so far on the vascular disease-AD axis, this work focus on selected aspects of it in the hope of identifying possible study designs to be applied to the vascular AD patient. Looking over the literature on AD-related vascular pathology, the need also emerges to find the right location of oxidative stress. Show more

Keywords: Alzheimer's disease, oxidative stress, vascular pathology

DOI: 10.3233/JAD-2011-111034

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 1-9, 2012

Authors: Ricci, Serafino | Fuso, Andrea | Ippoliti, Flora | Businaro, Rita

Article Type: Review Article

Abstract: Increasing evidence has been accumulating about the role of stress as an important challenge to the onset and progression of Alzheimer's disease (AD). The hippocampus, one of the areas of the brain damaged during AD, was the first brain region, besides the hypothalamus, to be recognized as a target of stress hormones, including cortisol, sympathetic and parasympathetic transmitters, cytokines, and metabolic hormones. The present review aims at summarizing neuroinflammatory mechanisms induced by stress, resulting in neuronal dysfunction and impaired neurogenesis. Lifestyle and environmental factors related to metabolic and inflammatory alterations observed in stressed subjects and thought to favor AD development …and progression, as well as the possible ways of prevention, are discussed. Show more

Keywords: Alzheimer's disease, cytokines, HPA axis, lifestyle, neurogenesis, stress

DOI: 10.3233/JAD-2011-110821

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 11-24, 2012

Authors: Michels, Andreas | Multhammer, Manuel | Zintl, Maria | Mendoza, Maria Cristina | Klünemann, Hans-Hermann

Article Type: Research Article

Abstract: To examine the relationship between apolipoprotein E ε4 (ApoE ε4) and psychiatric symptoms, we compared ε4/ε4, ε3/ε3, and ε3/ε4 subjects. 659 outpatients with memory complaints underwent comprehensive neuropsychiatric assessment interview and neurological examination and ApoE genotyping: 98 were ε4/ε4. 18.4% (n = 18) ε4/ε4, 19.3% (n = 45) ε3/ε4, and 5.4% (n = 14) ε3/ε3 presented with symptoms of anxiety (p = 0.00001). ε4/ε4 patients with mild cognitive impairment (MCI; p < 0.0001) and those with Alzheimer's disease with late onset (p = 0.0175) were the most frequently affected. For anxiety, there were no gender dependent differences in the two …homozygous groups, however, in the ε3/ε4 group, anxiety symptoms were evident in 7.3% (n = 8) of the male versus 30.1% (n = 37) of the female ε3/ε4 heterozygotes (p < 0.0001). Depression was found in 20.4% (n = 20) ε4/ε4 and 21.0% (n = 49) ε3/ε4 compared to 17.1% (n = 44) ε3/ε3 (p = 0.5181). Visual hallucinations were reported in 5.1% (n = 5) ε4/ε4 as opposed to 3.8% (n = 9) ε3/ε4 and 2.3% (n = 6) ε3/ε3 (p = 0.5278). We have seen a higher association of anxiety with the ApoE ε4 allele across all stages of disease and what may be a dosing effect in the early stage (MCI) for this ostensible risk, since we see a significantly higher frequency in the ApoE ε4 homozygotes when compared to the heterozygotes. Show more

Keywords: Anxiety, apolipoprotein E ε4 (ApoE ε4), ApoE ε4 homozygosity, delusion, depression, ε4/ε4 homozygosity, ε4/ε4 homozygous, hallucinations, psychiatric symptoms

DOI: 10.3233/JAD-2011-110554

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 25-32, 2012

Authors: Khalifat, Nada | Puff, Nicolas | Dliaa, Mariam | Angelova, Miglena I.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a degenerative disease of the central nervous system which causes irreversible damage to neuron structure and function. The main hypothesis concerning the cause of AD is excessive accumulation of amyloid-β peptides (Aβ). There has recently been a surge in studies on neuronal morphological and functional pathologies related to Aβ-induced mitochondrial dysfunctions and morphological alternations. What is the relation between the accumulation of Aβ in mitochondria, decreased production of ATP, and the large number of mitochondria with broken or scarce cristae observed in AD patients' neurons? The problem is complex, as it is now widely recognized that …mitochondria function determines mitochondrial inner membrane (IM) morphology and, conversely, that IM morphology can influence mitochondrial functions. In our previous work, we designed an artificial mitochondrial IM, a minimal model system (giant unilamellar vesicle) mimicking the IM. We showed experimentally that modulation of the local pH gradient at the membrane level of cardiolipin-containing vesicles induces dynamic membrane invaginations similar to the mitochondrial cristae. In the present work we show, using our artificial IM, that Aβ renders the membrane unable to support the formation of cristae-like structures when local pH gradient occurs, leading to the failure of this cristae-like morphology. Fluorescent probe studies suggest that the dramatic change of membrane mechanical properties is due to Aβ-induced lipid bilayer dehydration, increased ordering of lipids, loss of membrane fluidity, and possibly to Aβ-induced changes in dynamic friction between the two leaflets of the lipid membrane. Show more

Keywords: Alzheimer's disease, amyloid-β peptide (Aβ42), biophysical phenomena, fluorescence polarization, lipid bilayers, liposomes, micromanipulation, mitochondria, pH gradient, videomicroscopy

DOI: 10.3233/JAD-2011-110389

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 33-47, 2012

Authors: Bohrmann, Bernd | Baumann, Karlheinz | Benz, Jörg | Gerber, Francoise | Huber, Walter | Knoflach, Frédéric | Messer, Jürg | Oroszlan, Krisztina | Rauchenberger, Robert | Richter, Wolfgang F. | Rothe, Christine | Urban, Margit | Bardroff, Michael | Winter, Michael | Nordstedt, Christer | Loetscher, Hansruedi

Article Type: Research Article

Abstract: The amyloid-β lowering capacity of anti-Aβ antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid-β removal is controversial, antibody-mediated sequestration of peripheral Aβ versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful Aβ immunotherapy, we hypothesized that high affinity antibody binding to amyloid-β plaques and recruitment of brain effector cells is required for most efficient amyloid clearance. Here we report the generation of a novel fully human anti-Aβ antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to …a conformational epitope expressed on amyloid-β fibrils using HuCAL® phage display technologies. In peptide maps, both N-terminal and central portions of Aβ were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal Aβ bound to the complementarity determining regions was identified by x-ray analysis of a gantenerumab Fab-Aβ1-11 complex. In functional assays gantenerumab induced cellular phagocytosis of human amyloid-β deposits in AD brain slices when co-cultured with primary human macrophages and neutralized oligomeric Aβ42 -mediated inhibitory effects on long-term potentiation in rat brain. In APP751swedish xPS2N141I transgenic mice, gantenerumab showed sustained binding to cerebral amyloid-β and, upon chronic treatment, significantly reduced small amyloid-β plaques by recruiting microglia and prevented new plaque formation. Unlike other Aβ antibodies, gantenerumab did not alter plasma Aβ suggesting undisturbed systemic clearance of soluble Aβ. These studies demonstrated that gantenerumab preferentially interacts with aggregated Aβ in the brain and lowers amyloid-β by eliciting effector cell-mediated clearance. Show more

Keywords: Alzheimer's disease, Aβ, amyloid-β, antibody, HuCAL®, immunotherapy

DOI: 10.3233/JAD-2011-110977

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 49-69, 2012

Authors: Chen, Shuang-Qing | Cai, Qing | Shen, Yu-Ying | Wang, Pei-Jun | Teng, Gao-Jun | Li, Ming-Hua | Zhang, Wei | Zang, Feng-Chao

Article Type: Research Article

Abstract: The aim of this work was to explore the applicable value of 1 H-MRS evaluation on the treatment of Alzheimer's disease (AD) with neural stem cell (NSC) transplantation by quantitative analysis of metabolite changes in the hippocampal area in AβPP/PS1 transgenic (tg) mice. The tg mice (n = 30) aged 12 months were randomized into two subgroups: One receiving NSCs and the other receiving PBS transplantation in the bilateral hippocampal CA1 region. The wild-type mice (n = 15) were used as the control group. 1 H-MRS was performed before transplantation and 6 weeks after transplantation to measure the change of …N-acetylaspartate (NAA), myo-inositol (mI), glutamate (Glu), choline (Cho), and creatine (Cr) in the hippocampus. Results showed NAA and Glu levels were increased and mI level was decreased in NSC group compared with the PBS group at six weeks after transplantation (p < 0.05). There was no significant difference in NAA and Glu (p > 0.05), and there was significant difference in mI (p < 0.05) between NSC and control groups. However, there was no significant difference in Cho before and after transplantation among the three groups (p > 0.05). Histology showed the number of neurons in the hippocampal CA1 region increased significantly in the NSC group than those in the PBS group (p < 0.05), and the number of astrocytes significantly decreased in the NSC group compared with the PBS group. Ultrastructure showed that the neurons in the NSC group were morphologically normal. In conclusion, 1 H-MRS can display intracranial metabolite changes before and after NSC transplantation in tg mice and has a applicable value in evaluating the therapeutic effect of NSCs on AD. Show more

Keywords: Magnetic resonance spectroscopy (MRS), neural stem cells (NSCs), transplantation

DOI: 10.3233/JAD-2010-110893

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 71-80, 2012

Authors: Farr, Susan A. | Price, Tulin O. | Dominguez, Ligia J. | Motisi, Antonio | Saiano, Filippo | Niehoff, Michael L. | Morley, John E. | Banks, William A. | Ercal, Nuran | Barbagallo, Mario

Article Type: Research Article

Abstract: Polyphenols are potent antioxidants found in extra virgin olive oil (EVOO); antioxidants have been shown to reverse age- and disease-related learning and memory deficits. We examined the effects of EVOO on learning and memory in SAMP8 mice, an age-related learning/memory impairment model associated with increased amyloid-β protein and brain oxidative damage. We administered EVOO, coconut oil, or butter to 11 month old SAMP8 mice for 6 weeks. Mice were tested in T-maze foot shock avoidance and one-trial novel object recognition with a 24 h delay. Mice which received EVOO had improved acquisition in the T-maze and spent more time with …the novel object in one-trial novel object recognition versus mice which received coconut oil or butter. Mice that received EVOO had improve T-maze retention compared to the mice that received butter. EVOO increased brain glutathione levels suggesting reduced oxidative stress as a possible mechanism. These effects plus increased glutathione reductase activity, superoxide dismutase activity, and decreased tissue levels of 4-hydroxynoneal and 3-nitrotyrosine were enhanced with enriched EVOO (3 × and 5 × polyphenols concentration). Our findings suggest that EVOO has beneficial effects on learning and memory deficits found in aging and diseases, such as those related to the overproduction of amyloid-β protein, by reversing oxidative damage in the brain, effects that are augmented with increasing concentrations of polyphenols in EVOO. Show more

Keywords: Extra virgin olive oil, learning, memory, object recognition, oxidative stress, SAMP8, T-maze

DOI: 10.3233/JAD-2011-110662

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 81-92, 2012

Authors: Calderón-Garcidueñas, Lilian | Kavanaugh, Michael | Block, Michelle | D'Angiulli, Amedeo | Delgado-Chávez, Ricardo | Torres-Jardón, Ricardo | González-Maciel, Angelica | Reynoso-Robles, Rafael | Osnaya, Norma | Villarreal-Calderon, Rodolfo | Guo, Ruixin | Hua, Zhaowei | Zhu, Hongtu | Perry, George | Diaz, Philippe

Article Type: Research Article

Abstract: Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% …had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrPC ) was seen in highly exposed subjects. The down-regulation of the PrPC is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrPC and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders. Show more

Keywords: Alzheimer's disease, air pollution, cellular prion protein, children, inflammasomes, neuroinflammation, oxidative stress, particulate matter

DOI: 10.3233/JAD-2011-110722

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 93-107, 2012

Authors: Saxton, Judith | Hofbauer, Robert K. | Woodward, Michael | Gilchrist, Nigel L. | Potocnik, Felix | Hsu, Hai-An | Miller, Michael L. | Pejović, Vojislav | Graham, Stephen M. | Perhach, James L.

Article Type: Research Article

Abstract: Post hoc analyses suggest that memantine treatment may provide communication-related benefits in patients with Alzheimer's disease (AD). In this 12-week, international, randomized, double-blind, placebo-controlled trial of memantine (10 mg bid), the functional communication abilities of patients with AD (MMSE range: 10–19) were assessed using the Functional Linguistic Communication Inventory (FLCI; primary measure). Two combined subscales (Social Communication and Communication of Basic Needs) from the American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS; secondary measure) were administered to caregivers. Treatment-emergent adverse events were also recorded. After 12 weeks, memantine-treated patients (n = 133) demonstrated a non-significant improvement …on the FLCI (placebo: −0.6; memantine: 0.7; p = 0.070, LOCF) and a significant improvement on the ASHA FACS (placebo: −5.3; memantine: 0.5; p = 0.022), compared with placebo-treated patients (n = 124). Memantine had a low incidence of adverse events. In patients with moderate AD, memantine treatment improved functional communication, as recognized by caregivers. Show more

Keywords: Alzheimer's disease, American Speech-Language-Hearing Association Functional Assessment of Communication Skills for Adults (ASHA FACS), communication, drug therapy, Functional Linguistic Communication Inventory (FLCI), language, memantine, randomized controlled trial

DOI: 10.3233/JAD-2011-110947

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 109-118, 2012

Authors: Lewczuk, Piotr | Popp, Julius | Lelental, Natalia | Kölsch, Heike | Maier, Wolfgang | Kornhuber, Johannes | Jessen, Frank

Article Type: Research Article

Abstract: In this report, we confirm our previous findings of increased concentrations of soluble amyloid-β protein precursor (sAβPP) in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) in a large cohort of patients (n = 314), not overlapping with those of our previous study, and we extend our observations by including a control group of participants with normal cognition. In addition, we investigate the effects of age, the APOEε4 genotype, and the blood-CSF barrier function on the concentrations of sAβPPα and sAβPPβ. The study participants were categorized according to clinical-neuropsychological criteria, supported by CSF neurochemical …dementia diagnostics (NDD) analyses. sAβPPα concentrations in the AD group (132.0 ± 44.8) were significantly higher than in the control group (105.3 ± 37.3, p < 0.0005) but did not differ from the MCI-AD group (138.5 ± 39.5, p = 0.91). The MCI-AD group differed significantly from the MCI-O (97.3 ± 34.3, p < 0.05) group. There was no difference between the control and the MCI-O groups (p = 0.94). Similarly, sAβPPβ concentrations in the AD group (160.2 ± 54.3) were significantly higher than in the control group (129.9 ± 44.6, p < 0.005) but did not differ from the MCI-AD group (184.0 ± 56.4, p = 0.20). The MCI-AD group differed significantly from the MCI-O (127.8 ± 46.2, p < 0.05) group. There was no difference between the control and the MCI-O groups (p > 0.99). We observed highly significant correlation of the two sAβPP forms. Age and the CSF-serum albumin ratio were significant albeit weak predictors of the sAβPPα and sAβPPβ concentrations, while carrying the APOEε4 allele did not influenced the levels of the sAβPP forms. Taken together, the results strongly suggest that CSF sAβPP concentrations may be considered as an extension of already available NDD tools. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, biomarkers, cerebrospinal fluid

DOI: 10.3233/JAD-2011-110857

Citation: Journal of Alzheimer's Disease, vol. 28, no. 1, pp. 119-125, 2012