Journal of Alzheimer's Disease - Volume 45, issue 2

Authors: Luna-Muñoz, José | Perry, George | Guevara, Jorge

Article Type: Obituary

DOI: 10.3233/JAD-150134

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 325-327, 2015

Authors: Agostinho, Paula | Pliássova, Anna | Oliveira, Catarina R. | Cunha, Rodrigo A.

Article Type: Review Article

Abstract: Alzheimer's disease (AD) affects almost 35 million people worldwide. One of the neuropathological features of AD is the presence of extracellular amyloid plaques, which are mainly composed of amyloid-β (Aβ) peptides. These peptides derive from the amyloidogenic proteolytic processing of the amyloid-β protein precursor (AβPP), through the sequential action of β- and γ-secretases. However, AβPP can also be cleaved by a non-amyloidogenic pathway, involving an α-secretase, and in this case the Aβ formation is precluded. The production of Aβ and of other AβPP catabolites depends on the spatial and temporal co-localization of AβPP with α- or β-secretases and γ-secretase, which …traffic through the secretory pathway in a highly regulated manner. Disturbances on AβPP and secretases intracellular trafficking and, consequently, in their localization may affect dynamic interactions between these proteins with consequences in the AD pathogenesis. In this article, we critically review the recent knowledge about the trafficking and co-localization of AβPP and related secretases in the brain under physiological and AD conditions. A particular focus is given to data concerning the distribution of AβPP and secretases in different types of synapses relatively to other neuronal or glial localizations. Furthermore, we discuss some possible signals that govern the dynamic encounter of AβPP with each group of secretases, such as AβPP mutations, estrogen deprivation, chronic stress, metabolic impairment, and alterations in sleep pattern-associated with aging. The knowledge of key signals that are responsible for the shifting of AβPP processing away from α-secretases and toward the β-secretases might be useful to develop AD therapeutic strategies. Show more

Keywords: AβPP, AβPP-derived fragments, ADAM10, amyloid-β, BACE1, γ-secretase, presenilin

DOI: 10.3233/JAD-142730

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 329-347, 2015

Authors: Friedland, Robert P.

Article Type: Research Article

Abstract: The concept of molecular mimicry was established to explain commonalities of structure which developed in response to evolutionary pressures. Most examples of molecular mimicry in medicine have involved homologies of primary protein structure which cause disease. Molecular mimicry can be expanded beyond amino acid sequence to include microRNA and proteomic effects which are either pathogenic or salutogenic (beneficial) in regard to Parkinson's disease, Alzheimer's disease, and related disorders. Viruses of animal or plant origin may mimic nucleotide sequences of microRNAs and influence protein expression. Both Parkinson's and Alzheimer's diseases involve the formation of transmissible self-propagating prion-like proteins. However, the initiating …factors responsible for creation of these misfolded nucleating factors are unknown. Amyloid patterns of protein folding are highly conserved through evolution and are widely distributed in the world. Similarities of tertiary protein structure may be involved in the creation of these prion-like agents through molecular mimicry. Cross-seeding of amyloid misfolding, altered proteostasis, and oxidative stress may be induced by amyloid proteins residing in bacteria in our microbiota in the gut and in the diet. Pathways of molecular mimicry induced processes induced by bacterial amyloid in neurodegeneration may involve TLR 2/1, CD14, and NFκB, among others. Furthermore, priming of the innate immune system by the microbiota may enhance the inflammatory response to cerebral amyloids (such as amyloid-β and α-synuclein). This paper describes the specific molecular pathways of these cross-seeding and neuroinflammatory processes. Evolutionary conservation of proteins provides the opportunity for conserved sequences and structures to influence neurological disease through molecular mimicry. Show more

Keywords: Alzheimer's disease, amyloid, bacterial amyloid, metagenome, microbiota, neurodegenerative diseases, neuroinflammation, oxidative stress, Parkinson's disease

DOI: 10.3233/JAD-142841

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 349-362, 2015

Authors: Boncoraglio, Giorgio B. | Piazza, Fabrizio | Savoiardo, Mario | Farina, Laura | DiFrancesco, Jacopo C. | Prioni, Sara | Tagliavini, Fabrizio | Parati, Eugenio A. | Giaccone, Giorgio

Article Type: Short Communication

Abstract: Cerebral amyloid angiopathy-related inflammation (CAA-ri), a rare form of vasculitis associated with amyloid-β (Aβ) deposition in vessel walls, has been proposed as a spontaneous human model of the amyloid-related imaging abnormalities (ARIA) occurring after anti-Aβ immunotherapy for the treatment of Alzheimer's disease (AD). We describe a case of a patient with biopsy-proven CAA-ri and prodromal AD, confirmed by means of neuropsychological examination after 20 months follow-up, presenting with ARIA and high levels of cerebrospinal fluid anti-Aβ autoantibodies. This case further supports the analogies between the inflammatory response driven by anti-Aβ immunotherapy and that spontaneously occurring in CAA-ri.

Keywords: Alzheimer's disease, amyloid-related imaging abnormalities, anti-Aβ autoantibodies, cerebral amyloid angiopathy, cerebral amyloid angiopathy-related inflammation, subarachnoid hemorrhage

DOI: 10.3233/JAD-142376

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 363-367, 2015

Authors: Williams, Michael A. | Haughton, David | Stevenson, Michael | Craig, David | Passmore, A. Peter | Silvestri, Giuliana

Article Type: Short Communication

Abstract: Biomarkers for Alzheimer's disease (AD) should meet several criteria, including simplicity of testing. Inappropriate activation of the complement cascade has been implicated in the pathogenesis of AD. Complement factor H (CFH) is a regulator of the cascade, but studies on plasma CFH levels in AD have provided mixed results. This study compared plasma CFH levels in 317 AD cases with 254 controls using an immunodiffusion assay. The sample had an 80% power to detect a difference of 23 mg/L between cases and controls, but no difference was evident. Plasma CFH may not be a suitable biomarker for AD.

Keywords: Alzheimer's disease, biological markers, complement factor H

DOI: 10.3233/JAD-142742

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 369-372, 2015

Authors: Xia, Qin | Wang, Hongfeng | Zhang, Yan | Ying, Zheng | Wang, Guanghui

Article Type: Research Article

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, and progressive neurodegenerative disorder with no cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS; and aggresome formation of misfolded SOD1 is closely associated with ALS pathogenesis. HDAC6, one of the histone deacetylase family members, has already been demonstrated to play an important role in regulating aggresome formation of misfolded proteins and protecting cells against the toxicity induced by misfolded proteins. In this study, we found that in a cellular model with impaired proteasome activity, the TAR DNA-binding protein 43, which is closely linked with ALS and associated …with various neurodegenerative disorders such as frontotemporal lobar degeneration, Alzheimer's disease, and Parkinson's disease, can regulate mutant SOD1 aggresome formation through an HDAC6-dependent manner. TDP-43 deficiency did not affect poly-ubiquitination of mutant SOD1, whereas it greatly decreased the expression level of HDAC6, which is required for aggresome formation of ALS-linked mutant SOD1. Moreover, overexpression of siRNA-resistant HDAC6 restored mutant SOD1 aggresome formation in TDP-43-knockdown cells. Thus, our data provide evidence that TDP-43 plays an important role in mutant SOD1 aggresome formation through its regulation of HDAC6. Show more

Keywords: Aggresome, amyotrophic lateral sclerosis, histone deacetylase 6, superoxide dismutase 1, TAR DNA-binding protein-43

DOI: 10.3233/JAD-142244

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 373-386, 2015

Authors: Lattanzi, Simona | Luzzi, Simona | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: Background: The link between vascular disease and cognitive impairment is a matter of an ongoing debate, and different cardiovascular conditions have been found to be predictors of the clinical development and progression of cognitive dysfunction. Objective: To compare the influence of visit-to visit blood pressure (BP) variability on the rate of cognitive decline in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Methods: The patients affected by AD and FTD consecutively admitted to our center from January 2007 to September 2012 were evaluated every three months for a one-year period. The BP mean and coefficient of variation …as index of variability were obtained for both systolic and diastolic values. Progression of cognitive decline was investigated using the Mini-Mental State Examination administered at entry and at the end of the follow-up. Results: Two-hundred and forty-eight AD and eighty-one FTD patients were enrolled. Systolic and diastolic BP mean and variability were comparable between the two groups. Systolic BP variability (BPV) was associated with the rate of cognitive impairment in AD (B = 0.367, beta = 0.739, R2 = 0.594, adjusted R2 = 0.567; p < 0.001), but not in FTD patients; no relationship emerged between any other BP index and cognitive decline. Conclusion: The relationship between BPV and cognitive function is still not completely understood, and it may play different roles according to the types and stages of dementia. Fluctuations in systolic BP may contribute to the cognitive decline in AD patients and may represent a neglected therapeutic target. Show more

Keywords: Alzheimer's disease, blood pressure, dementia, frontotemporal dementia

DOI: 10.3233/JAD-142532

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 387-394, 2015

Authors: Remington, Ruth | Bechtel, Cynthia | Larsen, David | Samar, Annemarie | Doshanjh, Laura | Fishman, Paul | Luo, Yuan | Smyers, Kathleen | Page, Robert | Morrell, Christopher | Shea, Thomas B.

Article Type: Research Article

Abstract: Background: Increasing evidence points toward the efficacy of nutritional modifications in delaying cognitive decline and mood/behavioral difficulties in Alzheimer’s disease (AD). Nutritional supplementation with individual agents has shown varied results suggesting the need for combinatorial intervention. Objective: We set out to determine whether nutritional intervention could positively impact cognitive performance and behavioral difficulties for individuals diagnosed with AD. Methods: A double-blind, multi-site, phase II study (ClinicalTrials.gov NCT01320527; Alzheimer’s Association Trialmatch) was conducted in which 106 individuals with AD were randomized to a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or placebo for …3 or 6 months, followed by an open-label extension where participants received NF for 6 additional months. Results: The NF cohort improved versus the placebo cohort within 3 months (Clox-1 p = 0.0083, 95%CI [0.4481, 2.9343]; Dementia Rating Scale p = 0.0266, 95%CI [0.1722, 2.7171]). Caregivers reported non-significant improvements in Neuropsychiatric Inventory. Both cohorts improved or maintained baseline performance during open-label extensions. Activities of Daily Living did not change for either cohort. Conclusions: These findings extend phase I studies where NF maintained or improved cognitive performance and mood/behavior. Show more

Keywords: Acetyl-L-carnitine, Alzheimer's disease, B vitamins, behavioral difficulties, cognitive decline, N-acetyl cysteine, nutrition, supplement, S-adenosyl methionine, vitamin E

DOI: 10.3233/JAD-142499

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 395-405, 2015

Authors: Armand-Ugón, Mercedes | Aso, Ester | Moreno, Jesús | Riera-Codina, Miquel | Sánchez, Alex | Vegas, Esteban | Ferrer, Isidre

Article Type: Research Article

Abstract: Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AβPP/PS1 mouse model of familial Alzheimer's disease. Groups of 5-month-old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 UI/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative-PCR were used for gene expression studies. No alterations in …erythropoiesis were observed in CEPO-treated WT and AβPP/PS1 transgenic mice. EPO and CEPO improved memory in AβPP/PS1 animals. However, only EPO decreased amyloid-β (Aβ) plaque burden and soluble Aβ40 . Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor α1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AβPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AβPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission. Show more

Keywords: AβPP/PS1 transgenic mice, Alzheimer's disease, amyloid-β, carbamylated erythropoietin, erythropoietin, neurotransmitter receptors

DOI: 10.3233/JAD-141389

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 407-421, 2015

Authors: Wang, Xiaochuan | Blanchard, Julie | Tung, Yunn Chyn | Grundke-Iqbal, Inge | Iqbal, Khalid

Article Type: Research Article

Abstract: Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I1 PP2A ) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I1 PP2A can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) …carrying I1 PP2A . In the adult AAV1-I1 PP2A rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I1 PP2A animals, suggesting that I1 PP2A can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I1 PP2A induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I1 PP2A can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats. Show more

Keywords: Inhibitor I of PP2A (I1PP2A), neurofibrillary degeneration, protein phosphatase-2A (PP2A), tau hyperphosphorylation

DOI: 10.3233/JAD-142403

Citation: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 423-435, 2015