Journal of Alzheimer's Disease - Volume 38, issue 2

Authors: Laurén, Juha

Article Type: Review Article

Abstract: Soluble oligomeric species of amyloid-β (Aβ) peptide are presumed to be drivers of synaptic impairment, and the resulting cognitive dysfunction in Alzheimer's disease. In 2009, cellular prion protein (PrPC ) was identified in a genome-wide screen as a high-affinity receptor for Aβ oligomers, and since then, many studies have explored the role of PrPC in Alzheimer's disease. Herein, I systematically assess the current level of target validation for PrPC in Alzheimer's disease and the merits of the identified approaches to therapeutically affect the PrPC :Aβ oligomer-interaction. The interaction of Aβ oligomers with PrPC in mice impairs hippocampal …long-term potentiation, memory, and learning in a manner that involves Fyn, tau, and glutamate receptors. Furthermore, PrPC acts to catalyze the formation of certain Aβ oligomeric species in the synapse and may mediate the toxic effects of other β-sheet rich oligomers as well. Therapeutic approaches utilizing soluble PrPC ectodomain or monoclonal antibodies targeting PrPC can at least partially prevent the neurotoxic effects of Aβ oligomers in mice. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, c-fyn protein, prion protein

DOI: 10.3233/JAD-130950

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 227-244, 2014

Authors: Wang, Jiajia | Feng, Xuemei | Bai, Zhouxian | Jin, Lee-Way | Duan, Yong | Lei, Hongxing

Article Type: Short Communication

Abstract: Genetic studies have identified several genomic loci including chr19p13.2 relevant to Alzheimer's disease (AD) susceptibility. However, the functional roles of these genomic loci in AD pathogenesis require further clarification. Transcriptome as an endophenotype is critical for the understanding of disease mechanism. Here we demonstrate that chr19p is the most significantly perturbed chromosome region in AD brain transcriptome. With dual evidence from genome and transcriptome, chr19p likely play a special role in AD pathogenesis.

Keywords: Chromosome 19p, complement C3, gene expression, genetic association, KANK2

DOI: 10.3233/JAD-130917

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 245-250, 2014

Authors: Lee, Youngjeon | Kim, Young-Hyun | Park, Sang-Je | Huh, Jae-Won | Kim, Sang-Hyun | Kim, Sun-Uk | Kim, Ji-Su | Jeong, Kang-Jin | Lee, Kyoung-Min | Hong, Yonggeun | Lee, Sang-Rae | Chang, Kyu-Tae

Article Type: Research Article

Abstract: We reported previously that the intracerebroventricular streptozotocin (icv-STZ)-treated cynomolgus monkey showed regionally specific glucose hypometabolism in FDG-PET imaging, similar to that observed in the early stages of sporadic Alzheimer's disease (sAD). However, further pathological analyses of this model at the molecular level are needed to validate it as a feasible model for sAD. Two cynomolgus monkeys were injected with 2 mg/kg STZ into the cerebellomedullary cistern at day 1, 7 and 14. Two control monkeys were given normal saline. At 5 months after injection, the expression levels of genes encoding 9 upstream molecules in insulin/insulin-like growth factor (IGF) signaling and …markers for 4 cell-type populations in the frontal cortex, hippocampus, posterior cingulate, precuneus, and occipital cortex of control and icv-STZ treated cynomolgus monkeys were examined. Real-time quantitative PCR analyses demonstrated that the overall mRNA expression of insulin/IGF signaling-related genes was mainly impaired in the anterior part of the cerebrum, frontal cortex, and hippocampus, similar to the early stage of sAD. The changes were accompanied by the loss of oligodendrocytes and neurons. The posterior part of the cerebrum did not show degenerative alterations. The present study provides important fundamental information on the icv-STZ monkey model for sAD. These results may help guide future studies using this model for the investigation of pathological mechanisms and the development of drugs for sAD. Show more

Keywords: Alzheimer's disease, brain, insulin, monkey, real-time quantitative polymerase chain reaction, streptozotocin

DOI: 10.3233/JAD-130776

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 251-267, 2014

Authors: Zhang, Cong | Cheng, Yufang | Wang, Haitao | Wang, Chuang | Wilson, Steven P. | Xu, Jiangping | Zhang, Han-Ting

Article Type: Research Article

Abstract: Phosphodiesterase-4 (PDE4) inhibitors enhance memory, increase hippocampal neurogenesis, and reverse amyloid-β (Aβ)-induced memory deficits. Here, we examined whether long-form PDE4D knockdown by lentiviral RNA construct containing a specific microRNA/miRNA-mir hairpin structure (4DmiRNA) reversed memory impairment caused by amyloid-β1-42 (Aβ42 ) in mice using the Morris water maze (MWM) and novelty object recognition tests. Western blotting analysis was used to assess protein levels of cAMP response element-binding protein (CREB, unphosphorylated and phosphorylated [pCREB]), brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) to explore the neurochemical mechanisms. Aggregated Aβ42 (0.5 μg/side) bilaterally infused in …dentate gyrus decreased cAMP levels (p < 0.01) and produced memory deficits in the MWM (p < 0.01) and object recognition tests (p < 0.01). Microinfusions of lentiviruses resulted in downregulated expression of PDE4D4 and 4D5 proteins and reversed Aβ42 -induced cAMP decline (p < 0.05) and memory deficits. Treatment also concomitantly increased pCREB (p < 0.05) and BDNF (p < 0.01) and reduced IL-1β (p < 0.05), TNF-α (p < 0.01), and NF-κB (p65) (p < 0.05) in the hippocampus of Aβ42 -challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimer's disease. Show more

Keywords: Alzheimer's disease, anti-inflammation, long-form PDE4D, memory, PDE4

DOI: 10.3233/JAD-122236

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 269-280, 2014

Authors: Severini, Cinzia | Passeri, Pamela Petrocchi | Ciotti, MariaTeresa | Florenzano, Fulvio | Possenti, Roberta | Zona, Cristina | Di Matteo, Anna | Guglielmotti, Angelo | Calissano, Pietro | Pachter, Joel | Mercanti, Delio

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease (AD), the most common age-related neurodegenerative pathology, is the abnormal extracellular deposition of neurotoxic amyloid-β (Aβ) peptides that accumulate in senile plaques. Aβ aggregates are toxic to neurons and are thought to contribute to neuronal loss. Evidence indicates that inflammation is involved in the pathophysiology of AD, and activation of glial cells by a variety of factors, including Aβ, appears to be a central event. Among molecules produced during inflammation associated with neuronal death, CCL2, also known as monocyte chemotactic protein-1 (MCP-1), seems to be particularly important. Indeed, CCL2 levels are higher in …the cerebrospinal fluid of patients with AD than in controls. In the present study, we demonstrated the protective effect of bindarit (which inhibits CCL2 synthesis) against both Aβ25-35 and Aβ1-42 -induced toxicity in primary mixed neural cultures. Bindarit (30–500 μM) reversed cell death induced by Aβ in a dose-dependent manner and reduced the transcription and release of CCL2 by astrocytes after Aβ treatment, as revealed by qRT-PCR, ELISA, and immunofluorescence staining. Astroglial activation and CCL2 release was induced by ATP released by damaged neurons through interaction with P2X7 receptors present on astrocyte surface. CCL2, interacting with its cognate receptor CCR2, present on neuron surface, strongly contributes to the toxic activity of Aβ. Bindarit was able to disconnect this neuro–glial interaction. Our results demonstrate the ability of bindarit to inhibit Aβ-induced neuronal death and suggest the potential role of CCL2 inhibitors in the treatment of neuroinflammatory/neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, amyloid-β toxicity, bindarit, CCL2, neuroinflammation

DOI: 10.3233/JAD-131070

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 281-293, 2014

Authors: Cid-Fernández, Susana | Lindín, Mónica | Díaz, Fernando

Article Type: Research Article

Abstract: Although many studies have demonstrated decline in attention and executive function (especially in inhibitory control) in healthy aging and Alzheimer's disease (AD), similar studies concerning mild cognitive impairment (MCI) are scarce. In the present study, we evaluated how the cognitive decline associated with amnestic MCI (aMCI) affects these processes, analyzing the N2 and P3 components of event-related potentials (ERPs) during the response (Go) and inhibition of response (NoGo) to different stimuli. ERPs were analyzed in 63 healthy and 30 aMCI adults (aged 50 to 87 years) during performance of a Go/NoGo auditory-visual attention-distraction task. aMCI adults showed poorer execution (longer …response times and fewer correct responses) and smaller Go-N2 and NoGo-N2 amplitudes than control adults, whereas P3 amplitudes and N2 and P3 latencies did not differ between the groups. These results show that aMCI is associated with decline in executive function and stimuli evaluation in working memory. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, attention, event-related potentials, inhibition, P300

DOI: 10.3233/JAD-130677

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 295-306, 2014

Authors: Peters, Frédéric | Villeneuve, Sylvia | Belleville, Sylvie

Article Type: Research Article

Abstract: The objective of this work was to assess the predictive accuracy of targeted neuroimaging and neuropsychological measures for the detection of incipient dementia in individuals with mild cognitive impairment (MCI), and to examine the potential benefit of combining both classes of measures. Baseline MRI measures included hippocampal volume, cortical thickness, and white matter hyperintensities. Neuropsychological assessment focused on different aspects of episodic memory (i.e., familiarity, free recall, and associative memory) and executive control functions (i.e., working memory, switching, and planning). Global and regional cortical thinning was observed in MCI patients who progressed to dementia compared to those who remained stable, …whereas no differences were found between groups for baseline hippocampal volume and white matter hyperintensities. The strongest neuroimaging predictors were baseline cortical thickness in the right anterior cingulate and middle frontal gyri. For cognitive predictors, we found that deficits in both free recall and recognition episodic memory tasks were highly suggestive of progression to dementia. Cortical thinning in the right anterior cingulate gyrus, combined to controlled and familiarity-based retrieval deficits, achieved a classification accuracy of 87.5%, a specificity of 90.9%, and a sensitivity of 83.3%. This predictive model including both classes of measures provided more accurate predictions than those based on neuroimaging or cognitive measures alone. Overall, our findings suggest that detecting preclinical Alzheimer's disease is probably best accomplished by combining complementary information from targeted neuroimaging and cognitive classifiers, and highlight the importance of taking into account both structural and functional changes associated with the disease. Show more

Keywords: Alzheimer's disease, cortical thickness, episodic memory, mild cognitive impairment

DOI: 10.3233/JAD-130842

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 307-318, 2014

Authors: Van der Mussele, Stefan | Mariën, Peter | Saerens, Jos | Somers, Nore | Goeman, Johan | De Deyn, Peter P. | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Behavioral disturbances belong to the core symptoms of dementia and are also common in mild cognitive impairment (MCI). The identification of sets of symptoms is clinically interesting, as interventions targeting syndromes may be more effective than the management of individual symptoms. Objective: This study aimed to identify, describe, measure, and compare the fundamental behavioral syndromes that underlie the observed behavioral symptoms in MCI and Alzheimer’s disease (AD). Methods: A cross-sectional analysis of baseline data from a prospective, longitudinal study on behavioral symptoms in MCI and dementia was performed. The study population consisted of 270 MCI …and 402 AD patients. Behavioral assessment was performed by means of Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory (CMAI), and Cornell Scale for Depression in Dementia (CSDD). Principal components factor analysis with Direct Oblimin rotation was carried out on the MFS score ≥5, seven cluster scores of the Behave-AD and the total scores of the CMAI and the CSDD. Results: We identified three factors explaining behavior in the MCI group: a depression, a psychosis, and an agitation syndrome. Similar factors were found in AD, but the order: an agitation, a depression, and a psychosis syndrome, respectively, and the structure differed slightly. Diurnal rhythm disturbances and frontal lobe symptoms loaded with the depression syndrome in MCI and in AD they loaded with the agitation syndrome. Behavioral syndromes correlated in AD, but not in MCI, and the prevalence and severity of the behavioral syndromes were higher in AD than in MCI, except for the severity of the depression syndrome. Conclusion: In both MCI and AD, three similar behavioral syndromes exist, but behavior in MCI is more dominated by a depression syndrome, while behavior in AD is more subject to an agitation syndrome. Show more

Keywords: Alzheimer's disease, Behave-AD, behavioral symptoms, Cohen-Mansfield agitation inventory, Cornell scale, dementia, factor analysis, mild cognitive impairment, syndromes

DOI: 10.3233/JAD-130596

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 319-329, 2014

Authors: Di Ieva, Antonio | Valli, Mikaeel | Cusimano, Michael D.

Article Type: Research Article

Abstract: Currently, no clinical or neuroradiological techniques have been validated to distinguish Alzheimer's disease (AD) from idiopathic normal pressure hydrocephalus (iNPH). Both share anatomical and clinical similarities: AD is a form of irreversible degenerative dementia, whereas the dementia manifested in iNPH is potentially “reversible” through various neurosurgical procedures. Hence, it is important to find specific imaging biomarkers that distinguish the two conditions. In addition, the ability to predict the response to neurosurgery in iNPH is something that has yet to be accomplished. In this systematic review, we describe and critically analyze the merits and drawbacks of the MR imaging parameters currently …used to distinguish AD from iNPH and assess ways to predict the response after treatment of iNPH. We conclude that the combination of different neuroimaging sequences as well as quantitative and qualitative parameters could provide new insight for better diagnosis and treatment of these two different diseases. Show more

Keywords: Alzheimer's disease, diagnostic imaging, idiopathic normal pressure hydrocephalus, magnetic resonance imaging, neuroimaging

DOI: 10.3233/JAD-130581

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 331-350, 2014

Authors: Anfossi, Maria | Colao, Rosanna | Gallo, Maura | Bernardi, Livia | Conidi, M. Elena | Frangipane, Francesca | Vasso, Franca | Puccio, Gianfranco | Clodomiro, Alessandra | Mirabelli, Maria | Curcio, Sabrina A.M. | Torchia, Giusi | Smirne, Nicoletta | Di Lorenzo, Raffaele | Maletta, Raffaele | Bruni, Amalia C.

Article Type: Research Article

Abstract: Background: LRRK2 mutations are common in familial and sporadic Parkinson’s disease (PD) cases. Objective: We present a screening of the most frequently mutated exons of LRRK2 in Calabrian population. Methods: Eighty-eight PD patients diagnosed according to standard criteria, underwent screening for LRRK2 mutations in exons 19, 21, 24, 25, 27, 29, 31, 32, 33, 35, 38, 40, 41, and 48. Results: Eight LRRK2 variations were identified in nine patients affected by PD, including three novel missense variations (p.Phe1227Leu, p.Gly1520Ala, p.Ile2020Ser) and five previously identified mutations (p.Ala1151Thr, IVS31+3A>G, p.Arg1514Gln, p.Gly2019Ser, p.Thr2356Ile). LRRK2 frequency mutations were …approximately 10.2% in all PD patients, 12% in familial, 8% in sporadic cases. The p.Gly2019Ser mutation was found in 2.3% of the total cohort and in 3.2% of sporadic cases. The clinical features of LRRK2-associated with PD in our patients were similar to those of idiopathic PD although most LRRK2 mutated patients presented with bradykinesia instead of tremor; 33.3% developed dementia. Conclusions: We identified three novel LRRK2 mutations and reported a higher frequency in Calabria compared to previously reported data possibly due to the relative genetic isolation of the Calabrian population. These findings contribute to the understanding of the role of LRKK2 variations in PD and provide additional genetic insight into this disease. Show more

Keywords: Dementia, frequency mutations, genetics association, LRRK2, neurodegenerative disease, Parkinson's disease

DOI: 10.3233/JAD-130689

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 351-357, 2014

Authors: Narme, Pauline | Clément, Sylvain | Ehrlé, Nathalie | Schiaratura, Loris | Vachez, Sylvie | Courtaigne, Bruno | Munsch, Frédéric | Samson, Séverine

Article Type: Research Article

Abstract: Although musical interventions have recently gained popularity as a non-pharmacological treatment in dementia, there is still insufficient evidence of their effectiveness. To investigate this issue, a single-center randomized controlled trial was conducted with forty-eight patients with Alzheimer's disease or mixed dementia to compare the effects of music versus cooking interventions in the emotional, cognitive, and behavioral domain, as well as on professional caregiver distress. Each intervention lasted four weeks (two one-hour sessions a week). Multi-component evaluations (with blind assessors) were conducted before, during, and after the interventions to assess their short and long-term effects (up to four weeks post interventions). …Analyses revealed that both music and cooking interventions led to positive changes in the patients' emotional state and decreased the severity of their behavioral disorders, as well as reduced caregiver distress. However, no benefit on the cognitive status of the patients was seen. While results did not demonstrate a specific benefit of music on any of the considered measures, the present study suggests the efficacy of two pleasant non-pharmacological treatments in patients with moderate to severe dementia. Our findings highlight the potential of such interventions in improving the well-being of patients living in residential care, as well as reducing caregiver distress. Show more

Keywords: Behavioral disorders, caregiver distress, cooking, dementia, mood, music, non-pharmacological treatment, nursing

DOI: 10.3233/JAD-130893

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 359-369, 2014

Authors: Pákáski, Magdolna | Fehér, Ágnes | Juhász, Anna | Drótos, Gergely | Fazekas, Örsike Csilla | Kovács, János | Janka, Zoltán | Kálmán, János

Article Type: Research Article

Abstract: Neurotransmitter enhancement therapy with acetylcholinesterase inhibitors (AChEIs) is a clinically proven approach for patients with Alzheimer's disease (AD). Donepezil is one of the three currently approved AChEIs for treating AD symptoms delaying the decline in cognitive function. In addition to cholinergic hypofunction, there are several factors in AD pathogenesis. For example, adipocytokines released from adipose tissue are also thought to play a role in the progress of dementia. Adipokines, i.e., leptin and adiponectin, are involved in the modulation of certain cognitive functions in the brain. The goal of our study was to elucidate effects of donepezil therapy on the serum …levels of certain adipokines, such as leptin and adiponectin in AD patients. Clinically diagnosed mild-to-moderate AD patients (n = 26) were involved in this open-labeled, single-center, prospective self-control study. ApoE polymorphism, serum adiponectin, leptin, LDL, HDL, triglyceride levels, and BMI were determined before and at 12 and 24 weeks intervals of donepezil treatment, respectively. Twenty-four weeks of donepezil treatment induced a linear decrease of serum leptin levels (p = 0.013) and a linear elevation of serum adiponectin levels (p = 0.007). BMI (p < 0.001) and abdominal circumference (p = 0.017) were significantly lower at 24 weeks as compared to control values. None of the other examined metabolic parameters were changed during the treatment period. This previously unrecognized serum adipokine regulating potential of donepezil may be relevant in its therapeutic, disease modifying effect in AD by transferring protective (by increasing serum adiponectin levels) and detrimental (by decreasing serum leptin levels) effects onto the neurodegenerative process at the same time. Show more

Keywords: Acetylcholinesterase inhibitor, adipokine, adiponectin, Alzheimer's disease, apolipoprotein E, body weight, dementia, donepezil, leptin

DOI: 10.3233/JAD-131139

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 371-377, 2014

Authors: Müller, Stephan | Mychajliw, Christian | Hautzinger, Martin | Fallgatter, Andreas J. | Saur, Ralf | Leyhe, Thomas

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by retrograde memory deficits primarily caused by dysfunction of the hippocampal complex. Unresolved questions exist concerning the time course of hippocampal involvement in conscious recollection of declarative knowledge, as reports of temporal gradients of retrograde amnesia have been inconclusive. The aim of this study was to examine whether the extent and severity of retrograde amnesia is mediated by retrieval frequency or, in contrast, whether it depends on the age of the memory according to the assumptions of the main current theories of memory formation. We compared recall of past public events in patients with AD …and healthy control (HC) individuals using the Historic Events Test (HET). The HET assesses knowledge about famous public events of the past 60 years divided into four time segments and consists of subjective memory rating, dating accuracy, and contextual memory tasks. Although memory for public events was impaired in AD patients, there was a strong effect of retrieval frequency across all time segments and both groups. As AD and HC groups derived similar benefits from greater retrieval frequency, cortical structures other than the hippocampal complex may mediate memory retrieval. These findings suggest that more frequently retrieved events and facts become more independent of the hippocampal complex and thus better protected against early damage of AD. This could explain why cognitive activity may delay the onset of memory decline in persons who develop AD. Show more

Keywords: Alzheimer's disease, cognitive impairment, historic events test, multiple trace theory, retrieval frequency, standard model of memory consolidation

DOI: 10.3233/JAD-130923

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 379-390, 2014

Authors: Serra, Laura | Fadda, Lucia | Perri, Roberta | Spanò, Barbara | Marra, Camillo | Castelli, Diana | Torso, Mario | Makovac, Elena | Cercignani, Mara | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: Constructional apraxia (CA) is often, but not always, observed in patients with Alzheimer's disease (AD). CA is usually explained by impairment of either basic perceptual and motor abilities, or executive functions. This study aims to evaluate the structural correlates of CA in AD. Forty-eight patients with AD and 20 healthy age-matched controls underwent a thorough neuropsychological investigation and an MRI scan to collect high-resolution T1-weighted data. Patients were classified as having (ADca) or not having (ADnonca) CA based on performance on the Freehand copying of drawings task. T1-weighted volumes were process according to the voxel based morphometry protocol, to assess …the presence of significant differences in local to grey matter volumes in patients compared to controls and in ADca compared to ADnonca. Post-hoc, the mean grey matter volume of clusters that resulted significantly different between groups was regressed against the neuropsychological scores in which the two patient groups performed differently. A pre-senile disease onset was significantly more frequent in patients with CA compared to ADnonca. ADca patients also showed worse performances than patients with ADnonca at some tests requiring the processing of visuo-spatial data and testing working memory. They also showed widespread reductions in grey matter volume, mainly located in areas known to be implicated in object recognition and localization, and in maintenance and re-orienting of spatial attention. These findings suggest that the occurrence of CA in AD is often associated with a peculiar clinical onset (i.e., pre-senile), neuropsychological profile, and distribution of grey matter atrophy. Show more

Keywords: Alzheimer's disease, constructional praxis, drawing tasks, voxel-based morphometry

DOI: 10.3233/JAD-130656

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 391-402, 2014

Authors: Saresella, Marina | Marventano, Ivana | Calabrese, Elena | Piancone, Federica | Rainone, Veronica | Gatti, Andrea | Alberoni, Margherita | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: An impairment of the microglial catabolic mechanisms allows amyloid-β (Aβ) accumulation in plaques within the brain in Alzheimer's disease (AD). Monocytes/macrophages (M/M) are activated in AD and migrate thorough the blood-brain barrier (BBB) trying to improve Aβ clearing. In the attempt to shed light on the role of M/M in AD, these cells were analyzed in patients with AD or mild cognitive impairment (MCI) and in age-matched healthy controls. Results obtained in Aβ42 -stimulated cell cultures showed that significantly higher percentages of inflammatory M/M (CD14+ CD16− CCR2++ CX3CR1low ) expressing toll like receptors (TLR) 2 and 4, as well as …IL-6 and CCR2, a chemokine favoring M/M migration through the BBB, are seen in AD. Confocal microscopy suggested the presence of MHC-II/Aβ42 complexes on AD M/M alone. Finally, TRL3- and TLR8-expressing and IL-23-producing M/M were increased in both AD and MCI compared to HC. These data indicate that M/M in AD are characterized by an inflammatory profile and are involved in the induction of both innate immune responses via TLR stimulation and of acquired immunity possibly secondarily to the presentation of Aβ peptides in an MHC-restricted fashion. Therapeutic approaches designed to interrupt these mechanism might prove beneficial. Show more

Keywords: Alzheimer's disease, cytokines, monocytes, neuroinflammation, toll-like receptors

DOI: 10.3233/JAD-131160

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 403-413, 2014

Authors: Parham, Christi | Auckland, Lisa | Rachwal, Jessica | Clarke, Douglas | Bix, Gregory

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), amyloid-β (Aβ) deposits in the cerebrovasculature can result in neurovascular dysfunction and/or cerebral amyloid angiopathy. The accumulation of Aβ in blood vessels can cause endothelial cell damage, resulting in impaired Aβ clearance by the blood-brain barrier. Additionally, impaired endothelial cell function can result in decreased angiogenesis in the brains of AD patients, affecting cognitive function. VEGF is a crucial mediator of angiogenesis and is deficient in AD brains thus promoting angiogenesis could be an important component of successful AD treatment. The C-terminal portion of the extracellular matrix proteoglycan perlecan, Domain V (DV), promotes brain-derived endothelial cell …proliferation and is proangiogenic in that it increases VEGFR2 expression and production of VEGF. In this study, we show that Aβ25-35 reduces proliferation of a mouse brain microvascular endothelial cell line (MBEC) in vitro and that DV and mouse LG3 (C-terminal fragment of DV) block these effects of Aβ25-35 . Additionally, we show that DV restores the ability of MBECs to form tube-like structures on Matrigel in the presence of Aβ25-35 and that this is α5β1 dependent. Interestingly, the reduction in tube-like structure formation by Aβ25-35 was not due to endothelial cell death, suggesting that Aβ25-35 induces the downregulation of a cell surface molecule required for adhesion events critical to the angiogenic process. We propose a model suggesting that DV works through both the α5β1 integrin receptor and VEGFR2 to increase VEGF production, causing competition with Aβ25-35 for VEGFR2 binding, thus ultimately increasing VEGF expression and restoring angiogenesis. This supports DV as a potential anti-amyloid therapy. Show more

Keywords: Alzheimer's disease, amyloid-β25-35, blood-brain barrier, extracellular matrix, integrins, perlecan

DOI: 10.3233/JAD-130683

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 415-423, 2014

Authors: Bobkova, Natalia V. | Garbuz, David G. | Nesterova, Inna | Medvinskaya, Natalia | Samokhin, Alexander | Alexandrova, Irina | Yashin, Valerii | Karpov, Vadim | Kukharsky, Michail S. | Ninkina, Natalia N. | Smirnov, Andrey A. | Nudler, Evgeny | Evgen'ev, Michael

Article Type: Research Article

Abstract: Brain deterioration resulting from “protein folding” diseases, such as the Alzheimer's disease (AD), is one of the leading causes of morbidity and mortality in the aging human population. Heat shock proteins (Hsps) constitute the major cellular quality control system for proteins that mitigates the pathological burden of neurotoxic protein fibrils and aggregates. However, the therapeutic effect of Hsps has not been tested in a relevant setting. Here we report the dramatic neuroprotective effect of recombinant human Hsp70 in the bilateral olfactory bulbectomy model (OBX mice) and 5XFAD mouse models of neurodegeneration. We show that intranasally-administered Hsp70 rapidly enters the afflicted …brain regions and mitigates multiple AD-like morphological and cognitive abnormalities observed in model animals. In particular, in both cases it normalizes the density of neurons in the hippocampus and cortex which correlates with the diminished accumulation of amyloid-β (Aβ) peptide and, in the case of 5XFAD mice, reduces Aβ plaque formation. Consistently, Hsp70 treatment also protects spatial memory in OBX and 5XFAD mice. These studies demonstrate that exogenous Hsp70 may be a practical therapeutic agent for treatment of neurodegenerative diseases associated with abnormal protein biogenesis and cognitive disturbances, such as AD, for which neuroprotective therapy is urgently needed. Show more

Keywords: 5XFAD mice, Alzheimer's disease, amyloid-β, bulbectomized mice, Hsp70

DOI: 10.3233/JAD-130779

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 425-435, 2014

Authors: Sun, Yong-Xin | Ji, Xunming | Mao, XiaoOu | Xie, Lin | Jia, Jianping | Galvan, Veronica | Greenberg, David A. | Jin, Kunlin

Article Type: Research Article

Abstract: Mammalian target of rapamycin (mTOR) signaling has been suggested to be effective in modifying cognitive status in animal models of Alzheimer's disease (AD), but little is known about its role in AD patients. We hereby tested whether mTOR signaling was activated and whether activated mTOR signaling was related to the degree of cognitive deficits in patients with AD. Autopsy brain hippocampal tissues were obtained from controls and patients with AD and Western blots were performed using antibodies against mTOR signaling molecules and RagC, an upstream component of mTOR complex 1 (mTORC1) signaling. We found that expression of mTOR/p-mTOR and its …downstream targets S6/p-S6 and Raptor/p-Raptor were expressed in the control and AD hippocampus. The expression levels of these signaling molecules were significantly increased in the hippocampus at the severe stages of AD, compared to controls and other stages of AD. Interestingly, Rictor expression level was unaltered. In addition, RagC was increased in the hippocampus at the early, moderate, and severe stages of AD. Our data indicate that mTORC1, but not mTORC2, was activated in the AD brains and that the level of mTOR signaling activation was correlated with cognitive severity of AD patients. Show more

Keywords: Alzheimer's disease, cognitive impairment, mTOR, RagC, rapamycin

DOI: 10.3233/JAD-131124

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 437-444, 2014

Authors: Buratti, Laura | Viticchi, Giovanna | Falsetti, Lorenzo | Cagnetti, Claudia | Luzzi, Simona | Bartolini, Marco | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: Epidemiological studies have suggested a pathophysiological link between obstructive sleep apnea syndrome (OSAS) and Alzheimer's disease (AD). The mechanism by which sleep disturbance can affect cognitive impairment is not clear. The aim of this study was to investigate whether AD patients with OSAS have an impairment in cerebrovascular disease markers. We included 69 patients without OSAS and 93 patients with OSAS. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). Pathological values of IMT and BHI were …significantly associated with the presence of OSAS (IMT > 1.0 mm: OR 2.98, 95%CI: 1.37–6.46; p < 0.05; BHI < 0.69: OR 5.25, 95%CI: 2.35–11.74; p < 0.05, multivariate adjusted analysis). Furthermore, the extent of cerebrovascular impairment was correlated with the severity of OSAS. The finding of alterations of cerebral vessel functional and anatomic status in AD patients with OSAS suggests the potential for effective treatment for sleep-related disturbances in a subgroup of AD patients. Show more

Keywords: Alzheimer's disease, carotid atherosclerosis, cerebral hemodynamics, obstructive sleep apnea, ultrasound

DOI: 10.3233/JAD-131046

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 445-453, 2014

Article Type: Other

DOI: 10.3233/JAD-131047

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 455-457, 2014