Journal of Alzheimer's Disease - Volume 22, issue 3

Authors: Vincent, Adele J. | Gasperini, Robert | Foa, Lisa | Small, David H.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is caused by the accumulation of amyloid-β (Aβ), which induces progressive decline in learning, memory, and other cognitive functions. Aβ is a neurotoxic protein that disrupts calcium signaling in neurons and alters synaptic plasticity. These effects lead to loss of synapses, neural network dysfunction, and inactivation of neuronal signaling. However, the precise mechanism by which Aβ causes neurodegeneration is still not clear, despite decades of intensive research. The role of astrocytes in early cognitive decline is a major component of disease pathology that has been poorly understood. Recent research suggests that astrocytes are not simply passive support …cells for neurons, but are active participants in neural information processing in the brain. Aβ can disrupt astrocytic calcium signaling and gliotransmitter release, processes that are vital for astrocyte-neuron communication. Therefore, astrocyte dysfunction may contribute to the earliest neuronal deficits in AD. Here we discuss emerging concepts in glial biology and the implications of astrocyte dysfunction on neurodegeneration in AD. Show more

Keywords: Glia, gliotransmitters, homeostatic plasticity, network dysfunction, neural networks, neurodegeneration, seizures, TNFα

DOI: 10.3233/JAD-2010-101089

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 699-714, 2010

Authors: Frisardi, Vincenza | Panza, Francesco | Seripa, Davide | Imbimbo, Bruno P. | Vendemiale, Gianluigi | Pilotto, Alberto | Solfrizzi, Vincenzo

Article Type: Review Article

Abstract: Recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from mild cognitive impairment to Alzheimer's disease (AD), reduced risk of AD, and decreased mortality in AD patients. Furthermore, the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. At present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids, and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA), and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may …be associated with a reduced risk of incident dementia and AD, while for vascular dementia, cognitive decline, and predementia syndromes, the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally support a protective role of these macronutrients against cognitive decline, dementia, and AD. We reviewed evidence on the possible mechanisms underlying the suggested protective role of MeDi against age-related changes in cognitive function, predementia syndromes, and dementia, examining the possible role of macronutrients and food nutrients of the MeDi and their nutraceutical properties in modulating the risk of cognitive decline. Although vascular variables are likely to be in the causal pathway between MeDi and dementia syndromes and should be considered as possible mediators, other nonvascular biological mechanisms (i.e., metabolic, oxidative, and inflammatory) may be invoked to explain the complex epidemiological association between MeDi and cognitive decline. Show more

Keywords: Alcohol consumption, Alzheimer's disease, dementia, dietary fatty acids, fruits and vegetables, Mediterranean diet, mild cognitive impairment, vascular dementia

DOI: 10.3233/JAD-2010-100942

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 715-740, 2010

Authors: Parihar, Mordhwaj S. | Brewer, Gregory J.

Article Type: Review Article

Abstract: Alzheimer's disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-β (Aβ) in plaques. However, an exclusively pathological role for Aβ is being challenged by new evidence for an essential function of Aβ at the synapse. Aβ protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Aβ is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of Aβ at the synapse. At …physiological levels, Aβ is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric Aβ40 and Aβ42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of Aβ are associated with synaptic failure and Alzheimer's disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial Aβ alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and Aβ independently decrease neuronal plasticity. Our laboratory has reported that Aβ, glutamate, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of Aβ on synaptic plasticity. Show more

Keywords: Aging, Alzheimer's disease, mitochondria, survival signaling, synapse

DOI: 10.3233/JAD-2010-101020

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 741-763, 2010

Authors: Broustal, Oriane | Camuzat, Agnès | Guillot-Noël, Lena | Guy, Nathalie | Millecamps, Stéphanie | Deffond, Didier | Lacomblez, Lucette | Golfier, Véronique | Hannequin, Didier | Salachas, François | Camu, William | Didic, Mira | Dubois, Bruno | Meininger, Vincent | Ber, Isabelle Le | Brice, Alexis | the French clinical and genetic research network on FTD/FTD-MND,

Article Type: Short Communication

Abstract: Rapid advances were made in the knowledge of amyotrophic lateral sclerosis (ALS) with the recent identification of TARDBP and FUS mutations in familial ALS. More recently, FUS-positive inclusions were found in a subset of TDP-43-negative frontotemporal lobar degeneration (FTLD) prompting us to analyze FUS in FTLD and FTLD-ALS patients. The p.Arg521His mutation was identified in a patient who initially had behavioral disorders and rapidly developed ALS. Although the frequency of mutations is low, our study enlarges the phenotypes associated with FUS mutations and shows that FUS could also play a direct pathogenic role in FTLD spectrum of diseases.

Keywords: Amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobar degeneration, FUS, FUS/TLS, MND, TARDBP, TDP-43

DOI: 10.3233/JAD-2010-100837

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 765-769, 2010

Authors: Borghi, Roberta | Piccini, Alessandra | Barini, Erica | Cirmena, Gabriella | Guglielmotto, Michela | Tamagno, Elena | Fornaro, Michele | Perry, George | Smith, Mark A. | Garuti, Anna | Tabaton, Massimo

Article Type: Research Article

Abstract: The activity of the β-secretase involved in the cleavage of amyloid-β (Aβ) is increased in sporadic late-onset Alzheimer's disease (AD). Whether the corresponding γ-secretase activity is altered is still uncertain. We evaluated mRNA expression and protein levels of presenilin 1 (PS1) and γ-secretase activity in the frontal cortex of 32 cases with late-onset sporadic AD and those of 29 control subjects. We found a significant increase in PS1 mRNA, protein levels and γ-secretase activity in AD cases. These findings suggest that upregulation of PS1 leads to Aβ overproduction and accumulation in sporadic AD.

Keywords: Alzheimer's disease, amyloid-β, γ-secretase, presenilin 1

DOI: 10.3233/JAD-2010-100729

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 771-775, 2010

Authors: Deli, Mária A. | Veszelka, Szilvia | Csiszár, Boglárka | Tóth, Andrea | Kittel, Ágnes | Csete, Mária | Sipos, Áron | Szalai, Anikó | Fülöp, Lívia | Penke, Botond | Ábrahám, Csongor S. | Niwa, Masami

Article Type: Research Article

Abstract: Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic …organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1–42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1–42 . Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease. Show more

Keywords: Amyloid-β, blood-brain barrier, brain endothelial cells, glia, pentosan polysulfate, permeability, rat, serum amyloid P component

DOI: 10.3233/JAD-2010-100759

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 777-794, 2010

Authors: Monfort, Pilar | Felipo, Vicente

Article Type: Research Article

Abstract: Amyloid-β (Aβ) rapidly impairs hippocampal long-term potentiation (LTP) and cognitive function in rats. We hypothesized that: a) Aβ-induced impairment of LTP would be due to impairment of the nitric oxide (NO)-cGMP pathway and AMPA receptor translocation; and b) treatment with the anti-inflammatory drug ibuprofen would restore the NO-cGMP pathway and LTP. The aims of this work were to assess whether ibuprofen prevents and/or rescues Aβ-induced LTP impairments in hippocampal slices and to analyze the role of the altered NO-cGMP-protein kinase G pathway and AMPA receptor phosphorylation and synaptic expression in the mechanisms by which Aβ impairs and ibuprofen restores LTP. …Aβ impairs tetanus-induced activation of guanylate cyclase and cGMP increase, preventing protein kinase G activation, phosphorylation of GluR1 in Ser845 and AMPA receptors translocation to synaptic membranes, which is responsible for LTP impairment by Aβ. Ibuprofen prevents LTP impairment by Aβ by restoring guanylate cyclase activation and increase in cGMP and, subsequently, activation of protein kinase G, phosphorylation of GluR1 in Ser845 and synaptic expression of AMPA receptors. Restoration of cGMP levels is enough to restore all this process as indicated by the fact that the cGMP analog 8-Br-cGMP also normalizes the function of this pathway and restores LTP in the presence of Aβ. These results indicate that Aβ impairs LTP by impairing the NO-cGMP pathway and that ibuprofen restores LTP by restoring this pathway. These data suggest that restoring cGMP levels may have therapeutic utility to improve cognitive function impaired by Aβ. Show more

Keywords: Alzheimer's disease, AMPA receptors, amyloid-β, cGMP-dependent protein kinase, GluR1, phosphorylation, synaptic plasticity

DOI: 10.3233/JAD-2010-101092

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 795-809, 2010

Authors: Richard, Edo | van Gool, Willem A. | Hoozemans, Jeroen J.M. | an Haastert, Elise S. v | Eikelenboom, Piet | Rozemuller, Annemieke J.M. | van de Berg, Wilma D.J.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) pathology is accompanied by abnormalities of the microvasculature. Despite the potential importance of morphometric changes in the cortical capillary network on neuronal dysfunction and cognitive impairment, few autopsy studies have addressed this issue. In the present study, we investigated morphological microvascular changes and capillary length density (CLD) in ten well-characterized AD patients compared to ten age-matched controls using virtual isotropic hemispheres. The CLD in the temporal cortex was increased by 33% in AD patients compared to controls (p = 0.04), whereas CLD in the occipital cortex was unchanged. An increase of CLD was correlated to a decrease …of cortical diameter in the temporal cortex (Pearson's r –0.62, p = 0.003), suggesting that the increase in temporal CLD results from, or contributes to cortical atrophy. In the occipital cortex, more string vessels, probably remnants of degenerated capillaries, were observed in AD patients than in controls (p = 0.004). An exploratory analysis suggests co-localization of Aβ and string vessels. Our data indicate that morphometric changes in the cortical capillary network occur in AD in a region-specific manner and may be related to cortical atrophy in the affected regions. Show more

Keywords: Amyloid-β, capillary length density, space balls, stereology, string vessels

DOI: 10.3233/JAD-2010-100849

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 811-818, 2010

Authors: Gahete, Manuel D. | Rubio, Alicia | Córdoba-Chacón, José | Gracia-Navarro, Francisco | Kineman, Rhonda D. | Avila, Jesús | Luque, Raúl M. | Castaño, Justo P.

Article Type: Research Article

Abstract: Ghrelin and neurotensin (NTS) are neuroendocrine peptides that exert opposite effects on food intake and energy homeostasis, but share comparable actions in improving memory and learning. Ghrelin and NTS mediate their effects via receptors with high evolutionary identity: two ghrelin G-protein coupled receptors (GPCRs; GHS-R1a/1b) and three NTS-receptors, two GPCRs (NTSR1/2) and one non-GPCR (NTSR3). Because ghrelin and NTS systems are tightly linked to energy balance regulation and cognitive processes, they have been proposed to be altered in Alzheimer's disease (AD), a dementia syndrome markedly influenced by the metabolic status. Although it has been demonstrated that ghrelin and NTS can …attenuate AD-related cognitive impairment, a comprehensive analysis of these systems in AD has not been conducted. Here, we used quantitative real time-RT-PCR to analyze expression of the ghrelin/NTS axis in one of the cortical regions most affected in AD, the temporal gyrus. Results unveiled a striking reduction of mRNA levels for ghrelin, and its newly discovered In2-ghrelin variant, as well as for the enzyme responsible for ghrelin acylation, ghrelin-O-acyltransferase and GHS-R1a, while expression of GHS-R1b was markedly increased. In addition, expression levels of NTSR1 and NTSR2 were profoundly decreased in AD, whereas mRNA levels of NTS only declined slightly, and those of NTSR3 (which is involved in neuronal apoptosis) did not vary. Taken together, our results provide the first quantitative evidence showing that ghrelin/NTS systems are markedly altered in the brain of AD patients, thereby suggesting that these systems may contribute to the severe cognitive deficit observed in this pathology. Show more

Keywords: Alzheimer's disease, brain temporal lobe, ghrelin, GHS-R, In2-ghrelin variant, neurotensin, NTSR

DOI: 10.3233/JAD-2010-100873

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 819-828, 2010

Authors: Gil-Bea, Francisco J. | Aisa, Barbara | Solomon, Alina | Solas, Maite | del Carmen Mugueta, Maria | Winblad, Bengt | Kivipelto, Miia | Cedazo-Mínguez, Angel | Ramírez, María J.

Article Type: Research Article

Abstract: The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting …that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-β levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD. Show more

Keywords: Aβ, cerebrospinal fluid, cortisol, frontal cortex, glucocorticoid receptor, mild cognitive impairment, mineralocorticoid receptor, Mini-Mental Status Examination

DOI: 10.3233/JAD-2010-100663

Citation: Journal of Alzheimer's Disease, vol. 22, no. 3, pp. 829-838, 2010