Journal of Alzheimer's Disease - Volume 21, issue 1

Authors: Kanoski, Scott E. | Zhang, Yanshu | Zheng, Wei | Davidson, Terry L.

Article Type: Research Article

Abstract: Cognitive impairment and Alzheimer's disease are linked with intake of a Western diet, characterized by high levels of saturated fats and simple carbohydrates. In rats, these dietary components have been shown to disrupt hippocampal-dependent learning and memory processes, particularly those involving spatial memory. Using a rat model, the present research assessed the degree to which consumption of a high-energy (HE) diet, similar to those found in modern Western cultures, produces a selective impairment in hippocampal function as opposed to a more global cognitive disruption. Learning and memory performance was examined following 90-day consumption of an HE-diet in three nonspatial discrimination …learning problems that differed with respect to their dependence on the integrity of the hippocampus. The results showed that consumption of the HE-diet impaired performance in a hippocampal-dependent feature negative discrimination problem relative to chow-fed controls, whereas performance was spared on two discrimination problems that do not rely on the hippocampus. To explore the mechanism whereby consuming HE-diets impairs cognitive function, we investigated the effect of HE-diets on the integrity of the blood-brain barrier (BBB). We found that HE-diet consumption produced a decrease in mRNA expression of tight junction proteins, particularly Claudin-5 and -12, in the choroid plexus and the BBB. Consequently, an increased blood-to-brain permeability of sodium fluorescein was observed in the hippocampus, but not in the striatum and prefrontal cortex following HE-diet access. These results indicate that hippocampal function may be particularly vulnerable to disruption by HE-diets, and this disruption may be related to impaired BBB integrity. Show more

Keywords: Alzheimer's disease, amyloid-β, blood-brain barrier, choroid plexus, dementia, high fat diet, hippocampus, learning, occasion setting, Western diet

DOI: 10.3233/JAD-2010-091414

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 207-219, 2010

Authors: Rolstad, Sindre | Nordlund, Arto | Eckerström, Carl | Gustavsson, Marie H. | Blennow, Kaj | Olesen, Pernille J. | Zetterberg, Henrik | Wallin, Anders

Article Type: Research Article

Abstract: The concepts of brain and cognitive reserve stem from the observation that premorbid factors (e.g., education) result in variation in the response to brain pathology. Potential early influence of reserve on pathology, as assessed using the cerebrospinal fluid biomarkers total tau (t-tau) and amyloid-β42 , and cognition was explored in mild cognitive impairment (MCI) patients who remained stable over a two-year period. A total of 102 patients with stable MCI grouped on the basis of educational level were compared with regard to biomarker concentrations and cognitive performance. Stable MCI patients with higher education had lower concentrations of t-tau as compared …to those with lower education. Also, educational level predicted a significant proportion of the total variance in t-tau concentrations. Our results suggest that higher education may offer protection against tauopathy. Show more

Keywords: Brain reserve, cognitive reserve, education, mild cognitive impairment, neurochemical biomarkers

DOI: 10.3233/JAD-2010-091012

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 221-228, 2010

Authors: Singh, Manjeet | Murthy, Ven | Ramassamy, Charles

Article Type: Research Article

Abstract: Acrolein is one of the by-products of lipid peroxidation. Due to its high reactivity, it is not only a marker of lipid peroxidation but could also be an initiator of oxidative stress by adducting cellular nucleophilic groups. In brains of Alzheimer's disease (AD) patients, levels of acrolein are significantly higher in vulnerable brain region and, on primary hippocampal culture, it is more toxic than 4-hydroxyl-nonenal. The toxicity of the amyloid-β peptide is mediated through the generation of hydrogen peroxide (H2 O2 ). The actions of H2 O2 include oxidative modifications of proteins, lipids, and DNA as observed in AD. …Bacopa monniera (BM) has a long history of use in India as a memory-enhancing therapy. The objective of our study was to investigate the neuroprotective effects of the standardized extracts of BM against acrolein and H2 O2 and to elucidate the mechanisms underlying this protection. Our results show that a pre-treatment with the BM extract protected the human neuroblastoma cell line SK-N-SH against H2 O2 and acrolein. We demonstrated that BM pre-treatment significantly inhibited the generation of intracellular reactive oxygen species in addition to preserving the mitochondrial membrane potential. BM pre-treatment also prevented the modifications of the activity of several redox regulated proteins, i.e., NF-κB, Sirt1, ERK1/2, and p66Shc, so as to favor cell survival in response to oxidative stress. Thus, our findings demonstrate that BM can protect human neuroblastoma cells against H2 O2 and acrolein through different mechanisms involved in the pathophysiology of AD and could have a therapeutic application in the prevention of AD. Show more

Keywords: Alzheimer's disease, Bacopa monniera, mitochondria, oxidative stress, redox regulation

DOI: 10.3233/JAD-2010-091729

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 229-247, 2010

Authors: Kamynina, Anna V. | Volpina, Olga M. | Medvinskaya, Natalya I. | Aleksandrova, Irina Ju. | Volkova, Tatyana D. | Koroev, Dmitriy O. | Samokhin, Aleksandr N. | Nesterova, Inna V. | Shelukhina, Irina V. | Kryukova, Elena V. | Tsetlin, Viktor I. | Ivanov, Vadim T. | Bobkova, Natalya V.

Article Type: Research Article

Abstract: We studied the ability of four non-conjugated α7-subunit fragments of the nicotinic acetylcholine receptor to induce an immune response and to protect memory in olfactory bulbectomized mice which demonstrate abnormalities similar to Alzheimer's disease (AD). Vaccination only with the α7-subunit fragment 173–193 was shown to rescue spatial memory, to restore the level of α7 acetylcholine receptors in the cortex, and to prevent an increase in the amyloid-β (Aβ) level in brain tissue in these animals. Antibodies against the peptide 173–193 were revealed in blood serum and cerebrospinal liquid in the bulbectomized mice. Passive immunization with mouse blood sera containing antibodies …to the peptide 173–193 also restored memory in bulbectomized animals. The observed positive effect of both active and passive immunization with the fragment of α7-subunit on memory of bulbectomized mice provides a new insight into an anti-AD drug design. Show more

Keywords: α7-subunit of the nicotinic acetylcholine receptor, Alzheimer's disease, amyloid-β, immunization, olfactory bulbectomized mice, peptide fragments, spatial memory

DOI: 10.3233/JAD-2010-091474

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 249-261, 2010

Authors: Seo, Ji-Seon | Leem, Yea-Hyun | Lee, Kang-Woo | Kim, Seung-Woo | Lee, Ja-Kyeong | Han, Pyung-Lim

Article Type: Research Article

Abstract: The transgenic mouse Tg2576 is widely used as a murine model of Alzheimer's disease (AD) and exhibits plaque pathogenesis in the brain and progressive memory impairments. Here we report that Tg2576 mice also have severe spinal cord deficits. At 10 months of age, Tg2576 mice showed a severe defect in the hindlimb extension reflex test and abnormal body trembling and hindlimb tremors when suspended by the tail. The frequency and severity of these abnormalities were overt at 10 months of age and became gradually worsened. On the foot-printing analysis, Tg2576 mice had shorter and narrower strides than the non-transgenic control. …Histological analyses showed that neuronal cells including cholinergic neurons in the lumbar cord of Tg2576 mice were severely reduced in number. At 16 months of age, Tg2576 mice showed high levels of amyloid-β accumulation in the spinal cord. Consistent with this, Tg2576 mice showed that lipid peroxidation levels were increased and mitochondrial metabolic activity were significantly reduced in the spinal cord. Administration of curcumin, a natural compound that has antioxidant properties, notably reversed motor function deficits of Tg2576 mice. The enhanced lipid peroxidation and neuronal loss in the lumbar cord was also partially suppressed by curcumin. Electron microscopic analysis revealed that the sciatic nerve fibers were severely reduced in number and were demyelinated in Tg2576 mice, which were partially rescued by curcumin. These results showed that Tg2576 mice display severe degeneration of motor neurons in the spinal cord and associated motor function deficits. Show more

Keywords: Motor neurons, reactive oxygen species, spinal cord, Tg2576

DOI: 10.3233/JAD-2010-091528

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 263-276, 2010

Authors: Rueda, Noemí | Llorens-Martín, María | Flórez, Jesús | Valdizán, Elsa | Banerjee, Pradeep | Trejo, Jose Luis | Martínez-Cué, Carmen

Article Type: Research Article

Abstract: Ts65Dn (TS) mice exhibit several phenotypic characteristics of human Down syndrome, including an increased brain expression of amyloid-β protein precursor (AβPP) and cognitive disturbances. Aberrant N-methyl-D-aspartate (NMDA) receptor signaling has been suspected in TS mice, due to an impaired generation of hippocampal long-term potentiation (LTP). Memantine, an uncompetitive NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease, is known to normalize LTP and improve cognition in transgenic mice with high brain levels of AβPP and amyloid-β protein. It has recently been demonstrated that acute injections of memantine rescue performance deficits of TS mice on a fear …conditioning test. Here we show that oral treatment of aged TS mice with a clinically relevant dose of memantine (30 mg/kg/day for 9 weeks) improved spatial learning in the water maze task and slightly reduced brain AβPP levels. We also found that TS mice exhibited a significantly reduced granule cell count and vesicular glutamate transporter-1 (VGLUT1) labeling compared to disomic control mice. After memantine treatment, the levels of hippocampal VGLUT1 were significantly increased, reaching the levels observed in vehicle treated-control animals. Memantine did not significantly affect granule cell density. These data indicate that memantine may normalize several phenotypic abnormalities in TS mice, many of which – such as impaired cognition – are also associated with Down syndrome and Alzheimer's disease. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, Down syndrome, memantine, Morris water maze, NMDA, spatial learning, Ts65Dn mice, vesicular glutamate transporter-1

DOI: 10.3233/JAD-2010-100240

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 277-290, 2010

Authors: Le Bastard, Nathalie | Leurs, Judith | Blomme, Walter | De Deyn and, Peter Paul | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: The objective of this study was to evaluate the diagnostic performance of full-length and N-truncated plasma amyloid-β (Aβ) forms in patients with Alzheimer's disease (AD) and non-Alzheimer's disease dementia (non-AD) as compared to healthy control subjects. Plasma samples from 50 AD, 50 non-AD, and 47 control subjects were included and analyzed using a multiparameter fluorimetric bead-based immunoassay for the simultaneous quantification of different Aβ forms. No significant differences in Aβ isoforms were detected between dementia and controls; or AD, non-AD, and controls. Compared to control subjects, pooled dementia patients (AD and non-AD) and AD patients alone had significantly lower plasma …Aβ1-42 /AβN-42 ratios. In each diagnostic group, all plasma Aβ concentrations were significantly correlated. No significant correlations between plasma Aβ forms and age were found. The low diagnostic performance of cross-sectional plasma Aβ measurements hampers future application as diagnostic markers or screening tools for dementia. CSF biomarker analysis remains superior, although the possible application of longitudinal plasma Aβ measurements as screening tools for dementia remains to be elucidated. Show more

Keywords: Alzheimer's disease, amyloid, biomarkers, non-Alzheimer's disease dementia, plasma

DOI: 10.3233/JAD-2010-091501

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 291-301, 2010

Authors: Poetsch, Verena | Neuhaus, Winfried | Noe, Christian Roland

Article Type: Research Article

Abstract: A disrupted blood-brain barrier (BBB) might have major effects on the progression of Alzheimer's disease (AD). This supports the theory of blood as a chronic source of exogenous amyloid-β (Aβ) peptide as well as other neurotoxic substances in the brain, which would normally be excluded by an intact BBB. In addition to Aβ, neuroinflammation is suggested to contribute to the pathological conditions in AD and is a known disruptor of BBB integrity. Consequently, new therapeutic approaches to stabilize the BBB should be developed. Serum derived immunoglobulins, also called intravenous immunoglobulins (IVIG), are gained from plasma of healthy individuals and were …found to induce positive effects in some patients with AD, but mechanisms of action are unclear by now. Moreover, there are no data on how IVIG affects the BBB itself. Therefore, we examined the potency of Aβ peptides as well as neuroinflammatory mediators (TNF-α and LPS) either alone or after simultaneous application of IVIG to disintegrate the BBB by evaluating the transport rate of carboxyfluorescein, a marker of paracellular leakage. Our results showed beneficial effects of IVIG on a disrupted BBB, which could positively influence diseases outcome in AD. With a stabilized BBB the brain is prevented from systemic Aβ entry, as well as from entry of other toxic substances from the blood. Show more

Keywords: Alzheimer's disease, amyloid peptide, blood-brain barrier, intravenous immunoglobulins

DOI: 10.3233/JAD-2010-090769

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 303-314, 2010

Authors: Strobel, Gabrielle

Article Type: Editorial

DOI: 10.3233/JAD-2010-100148

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 315-321, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-100212

Citation: Journal of Alzheimer's Disease, vol. 21, no. 1, pp. 323-324, 2010