Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Cao, Qin | Meng, Tian | Man, Jianhui | Peng, Dong | Chen, Hongxia | Xiang, Qi | Su, Zhijian | Zhang, Qihao | Huang, Yadong

Article Type: Research Article

Abstract: Glycogen synthase kinase 3β (GSK3β) is a key component of pathogenesis in Alzheimer’s disease, and its inhibitors can restore cognitive function as therapeutic interventions in neurodegenerative diseases. The previous studies showed that acidic fibroblast growth factor (aFGF) could increase the phosphorylation of GSK3β through the PI3K/Akt signaling pathway. We found that aFGF14–154 markedly increased the average length of neurites in neurons damaged by amyloid-β (Aβ), and this promoting effect was blocked by GSK3β inhibitor. It is still unknown which downstream substrates of GSK3β are related to the neurite growth facilitated by aFGF14-154 . The downstream substrates interacting with GSK3β …were screened by co-immunoprecipitation and LTQ-Orbitrap proteomics technology in our study. Collapsin response mediator protein 2 (CRMP2) has been identified as a protein interacting with GSK3β, which is involved in the axon formation and neuron regeneration by regulating microtubule reorganization. aFGF14-154 increased the phosphorylation of GSK3β (Ser9) to inhibit its activity, then was followed by a low phosphorylation level of CRMP2 (Thr514), which led to the neurite growth. The knockdown of CRMP2 blocked the rescue of aFGF14–154 with broken neurites and shrunken cell bodies in neurons with Aβ injury. These results highlight the important role of CRMP2 and its phosphorylation through GSK3β in the effect that aFGF14-154 promoted the growth of neurite damaged by Aβ. Show more

Keywords: Acidic fibroblast growth factor14-154, collapsin response mediator protein 2, glycogen synthase kinase 3β, neurons, CRMP2

DOI: 10.3233/JAD-190458

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Snowden, Stuart G. | Ebshiana, Amera A. | Hye, Abdul | Pletnikova, Olga | O’Brien, Richard | Yang, An | Troncoso, Juan | Legido-Quigley, Cristina | Thambisetty, Madhav

Article Type: Research Article

Abstract: Background: Cholinesterase inhibitors represent three of the four treatments for Alzheimer’s disease (AD), and target the pathological reduction of acetylcholine levels. Here we aimed to study the role of other neurotransmitter pathways in AD pathology. Objective: This study aimed to determine associations between AD pathology at both symptomatic and asymptomatic stages of disease progression, and the metabolism of a range of non-cholinergic neurotransmitters. Methods: Tissue samples were obtained from three groups, controls, AD, and ‘asymptomatic AD’ (ASYMAD), i.e., cognitively normal individuals that had significant AD neuropathology. Three brain areas were studied, the middle frontal gyrus (MFG), …the inferior temporal gyrus (ITG), and the cerebellum. Results: 12 of 15 metabolites involved in neurotransmitter metabolism were shown to be associated with AD pathology. Decreases in dopamine were most pronounced in the MFG with lower levels seen in the ASYMAD group compared to control (FC = 0.78, p  = 2.9×10–2 ). In the ITG significant changes were seen in GABAergic and serotonin metabolism between control and AD patients; however, these changes were not seen between control and ASYMAD individuals. Conclusion: These results indicate that dopamine could be depleted in brains with AD pathology but intact cognition, while an imbalance of several neurotransmitters is evident in the brains of AD patients. Show more

Keywords: Asymptomatic Alzheimer’s disease, brain, metabolomics, neurotransmitters

DOI: 10.3233/JAD-190577

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Pozueta, Ana | Lage, Carmen | Martínez, María García | Kazimierczak, Martha | Bravo, María | López-García, Sara | Riancho, Javier | González-Suarez, Andrea | Vázquez-Higuera, José Luis | de Arcocha-Torres, María | Banzo, Ignacio | Bonilla, Julio Jimenez | Berciano, José | Rodríguez-Rodríguez, Eloy | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: Background: Semantic dementia (SD) is a subtype of frontotemporal lobe degeneration characterized by semantic loss, with other cognitive functions initially preserved. SD requires differential diagnosis with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Semantic knowledge can be evaluated through different tests; however, most of them depend on language. Objective: We describe the development of a brief drawing task that may the helpful for the differential diagnosis of SD. Methods: Seventy-two patients, including 32 AD, 19 bvFTD, and 21 SD were asked to draw 12 items with different age of acquisition and familiarity, belonging to …four different semantic categories. We employed the drawings of healthy volunteers to build a scoring scheme. Results: Turtle, strawberry, train, and envelope were the items of each category that best discriminated between groups and were selected for the Brief drawing task. The discriminatory power of the Brief drawing task between SD versus AD and bvFTD patients, estimated through the area under the curve was 0.84 (95% CI = 0.72–0.96, p  = 0.000007). In a logistic model, the Brief drawing task (p  = 0.003) and VOSP “number location” subtest (p  = 0.016) were significant predictors of the diagnosis of SD versus AD and bvFTD after adjustment by the main covariates. The Brief drawing task provided clinically useful qualitative information. SD drawings were characterized by loss of the distinctive features, intrusions, tendency to prototype, and answers like “I don’t know what this is”. Conclusion: The Brief drawing task appears to reveal deficits in semantic knowledge among patients with SD that may assist in the differential diagnosis with other neurodegenerative diseases. Show more

Keywords: Dementia, differential diagnosis, drawings, semantic dementia, semantic knowledge

DOI: 10.3233/JAD-190660

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Jääskeläinen, Olli | Solje, Eino | Hall, Anette | Katisko, Kasper | Korhonen, Ville | Tiainen, Mika | Kangas, Antti J. | Helisalmi, Seppo | Pikkarainen, Maria | Koivisto, Anne | Hartikainen, Päivi | Hiltunen, Mikko | Ala-Korpela, Mika | Soininen, Hilkka | Soininen, Pasi | Haapasalo, Annakaisa | Remes, Anne M. | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract:  Decreased levels of serum high-density lipoprotein (HDL) cholesterol have previously been linked to systemic inflammation and neurodegenerative diseases, such as Alzheimer’s disease. Here, we aimed to analyze the lipoprotein profile and inflammatory indicators, the high-sensitivity C-reactive peptide (hs-CRP) and glycoprotein acetyls (GlycA), in sporadic and C9orf72 repeat expansion-associated frontotemporal lobar degeneration (FTLD) patients. The C9orf72 hexanucleotide repeat expansion is the most frequent genetic etiology underlying FTLD. The concentrations of different lipid measures in the sera of 67 FTLD patients (15 C9orf72 repeat expansion carriers), including GlycA, were analyzed by nuclear magnetic resonance spectroscopy. To verify the state …of systemic inflammation, hs-CRP was also quantified from patient sera. We found that the total serum HDL concentration was decreased in C9orf72 repeat expansion carriers when compared to non-carriers. Moreover, decreased concentrations of HDL particles of different sizes and subclass were consistently observed. No differences were detected in the very low- and low-density lipoprotein subclasses between the C9orf72 repeat expansion carriers and non-carriers. Furthermore, hs-CRP and GlycA levels did not differ between the C9orf72 repeat expansion carriers and non-carriers. In conclusion, the HDL-related changes were linked with C9orf72 repeat expansion associated FTLD but were not seen to associate with systemic inflammation. The underlying reason for the HDL changes remains unclear. Show more

Keywords: C9orf72 protein, cholesterol, frontotemporal dementia, frontotemporal lobar degeneration, inflammation, lipoproteins

DOI: 10.3233/JAD-190132

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Wang, Yiran | Wang, Ying | Bharti, Veni | Zhou, Hong | Hoi, Vanessa | Tan, Hua | Wu, Zijian | Nagakannan, Pandian | Eftekharpour, Eftekhar | Wang, Jun-Feng

Article Type: Research Article

Abstract: Oxidative stress has been hypothesized to play a role in the pathophysiology of Alzheimer’s disease (AD). Previously, we found that total nitrosylated protein levels were increased in the brain of amyloid-β protein precursor (AβPP) and presenilin 1 (PS1) double transgenic mice, an animal model for AD, suggesting that cysteine oxidative protein modification may contribute to this disease. Thioredoxin (Trx) is a major oxidoreductase that can reverse cysteine oxidative modifications such as sulfenylation and nitrosylation, and inhibit oxidative stress. Thioredoxin-interacting protein (Txnip) is an endogenous Trx inhibitor. To understand the involvement of Trx and Txnip in AD development, we investigated Trx …and Txnip in the brain of AβPP/PS1 mice. Using immunoblotting analysis, we found that although Trx protein levels were not changed, Txnip protein levels were significantly increased in hippocampus and frontal cortex of 9- and 12-month-old AβPP/PS1 mice when compared to wild-type mice. Txnip protein levels were also increased by amyloid-β treatment in primary cultured mouse cerebral cortical neurons and HT22 mouse hippocampal cells. Using biotin switch and dimedone conjugation methods, we found that amyloid-β treatment increased protein nitrosylation and sulfenylation in HT22 cells. We also found that downregulation of Txnip, using CRISPR/Cas9 method in HT22 cells, attenuated amyloid-β-induced protein nitrosylation and sulfenylation. Our findings suggest that amyloid-β may increase Txnip levels, subsequently inhibiting Trx reducing capability and enhancing protein cysteine oxidative modification. Our findings also indicate that Txnip may be a potential target for the treatment of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , nitrosylation, oxidative stress, sulfenylation, thioredoxin, thioredoxin-interacting protein

DOI: 10.3233/JAD-190223

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Pang, Rui Qi | Wang, Xiao Fan | Pei, Fei Fei | Zhang, Weizhe | Shen, Jiaming | Gao, Xiaoqun | Chang, Cheng

Article Type: Research Article

Abstract: Brain energy metabolic impairment is one of the main features of Alzheimer’s disease (AD) and is considered an underlying factor involved in cognitive impairment. Therefore, brain energy metabolism may represent a new therapeutic target for AD medical interventions. Among nutrients providing energy, glucose, the primary energy source, cannot cross the blood-brain barrier freely without specific glucose transporters (GLUTs), which are essential for the maintenance of cerebral energy metabolism homeostasis. Several converging lines of evidence suggest that GLUT1 deficiency in mice leads to synapse reduction and dysregulation coupled with mitochondrial morphological changes. In this study, the results revealed that regular exercise …(RE) decreased the expression of amyloid-β and phosphorylated tau by western blot, and enhanced the spatial learning and exploration ability of AD model mice as assessed by Morris water maze test. Mitochondrial cristae and edges were clear and intact, ATP production in the brain raised, the number of synapses increased, and GLUT1 and GLUT3 expression levels improved in the central nervous system (CNS) in AD model mice after RE. Changes in GLUT1 and GLUT3 expression at the protein level after RE are an important part of energy metabolic adaptation in AD model mice. Learning and memory improvement are highly associated with mitochondrial integrity and sufficient synapses in the CNS. This research suggests that increased brain energy metabolism attributed to RE exhibits promising therapeutic potential for AD. Show more

Keywords: Alzheimer’s disease, energy metabolism, glucose transporter, mitochondria, synapse

DOI: 10.3233/JAD-190328

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Serra, Laura | Petrosini, Laura | Salaris, Andrea | Pica, Lorenzo | Bruschini, Michela | Di Domenico, Carlotta | Caltagirone, Carlo | Marra, Camillo | Bozzali, Marco

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) explains the individual resilience to neurodegeneration. Years of formal education express the static measure of reserve (sCR). A dynamic aspect of CR (dCR) has been recently proposed. Objective: The aim of the study was to compare sCR and dCR indexes, respectively, to detect brain abnormalities in Alzheimer’s disease (AD) patients. Methods: 117 individuals [39 AD, 40 amnestic mild cognitive impairment (aMCI), 38 healthy subjects (HS)] underwent neuropsychological evaluation and a 3T-MRI. T1-weighted volumes were used for manual segmentation of the hippocampus and of the parahippocampal cortices. Years of formal education were used …as an index of sCR. Partial Least Square analysis was used to decompose the variance of individual MMSE scores, considered as a dCR index. In aMCI and AD patients, the brain abnormalities have been assessed comparing individuals with high and low levels of sCR and dCR in turn. Moreover, we investigated the effect of the different CR indexes in mediating the relationship between changes in brain volumes and memory performances. Results: sCR and dCR indexes classified differently individuals having high or low levels of CR. Smaller hippocampal and parahippocampal volumes in high dCR patients were found. The sCR and dCR indexes mediated significantly the relationship between brain abnormalities and memory in patients. Conclusions: CR mediated the relationship between brain and memory dysfunctions. We hypothesized that sCR and dCR indexes are a representation of different warehouses of reserve not operating in parallel but forming a complex system, in which crystalized cognitive abilities and actual cognitive efficiency interact with brain atrophy impacting on memory. Show more

Keywords: Alzheimer’s disease, dynamic and static cognitive reserve, hippocampus, mild cognitive impairment, parahippocampal gyrus

DOI: 10.3233/JAD-190716

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Rhea, Elizabeth M. | Nirkhe, Surabhi | Nguyen, Steven | Pemberton, Sarah | Bammler, Theo K. | Beyer, Richard | Niehoff, Michael L. | Morley, John E. | Farr, Susan A. | Banks, William A.

Article Type: Research Article

Abstract: Research on intranasal delivery of drugs, peptides, and proteins has grown over the past decade as an alternate way to deliver substrates to the brain. Recent work has shown intranasal (INL) delivery of insulin improves memory and cognition in healthy subjects as well as patients with Alzheimer’s disease (AD) and in AD mouse models. However, the molecular mechanism(s) for the beneficial effect of insulin on memory are still unclear. Using the SAMP8 mouse model of AD, we investigated the impact of INL insulin on protein and gene expression in brain regions including the olfactory bulb, hypothalamus, and hippocampus. We found …genes and proteins in the insulin receptor signaling pathway were not activated by the doses tested. However, we did find the expression of genes present in the hippocampus involved in other pathways, especially those related to inflammation, were altered due to age and with a dose of INL insulin previously shown to improve cognition. These alternate pathways could be targets of insulin when delivered via the INL route to aid in memory improvement. Show more

Keywords: Alzheimer’s disease, cognition, hippocampus, insulin, intranasal, RNA sequence analysis

DOI: 10.3233/JAD-190707

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Kulshreshtha, Ambar | Goetz, Margarethe | Alonso, Alvaro | Shah, Amit J. | Douglas Bremner, J. | Goldberg, Jack | Vaccarino, Viola

Article Type: Research Article

Abstract: Background/Objective: The 2020 Strategic Impact Goal introduced by the American Heart Association (AHA) aims at improving cardiovascular health (CVH) of all Americans by 20%. AHA defined ideal CVH across seven established modifiable risk factors for cardiovascular diseases. Prior studies have indicated that ideal CVH also benefits brain health and cognitive aging, but it is possible that this association is explained by familial factors. Methods: We examined 272 male monozygotic and dizygotic twin pairs (total 544 subjects) free of overt cardiovascular disease and dementia from the Vietnam Era Twin Registry. Memory and learning were measured by Trail Making tests …and Wechsler Memory Scale (Immediate and Delayed Memory tests and Visual Reproductive Test). Each of the seven CVH components (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and blood glucose) was scored per established criterion. Results: The mean age of the twins was 55 years, 96% were whites, and 61% monozygotic. When considering twins as individuals, for every unit increase in CVH score (indicating better cardiovascular health), twins demonstrated faster cognitive processing speed (Trail B: – 5.6 s, 95% CI – 10.3, – 0.9; p  = 0.03) and better story recall, both immediate (0.35, 95% CI 0.06, 0.62; p  = 0.02) and delayed (0.39, 95% CI 0.08, 0.70; p  = 0.01). Conclusions: Better CVH is associated with better cognitive health in several domains. As suggested by within-pair analysis, this association is largely explained by familial factors, implying that early life exposures are shared determinants of both brain health and cardiovascular health. Show more

Keywords: Epidemiology, prevention, risk factors

DOI: 10.3233/JAD-190217

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Fagiani, Francesca | Lanni, Cristina | Racchi, Marco | Pascale, Alessia | Govoni, Stefano

Article Type: Review Article

Abstract: It is now more than two decades since amyloid-β (Aβ ), the proteolytic product of the amyloid-β protein precursor (Aβ PP), was first demonstrated to be a normal and soluble product of neuronal metabolism. To date, despite a growing body of evidence suggests its regulatory role on synaptic function, the exact cellular and molecular pathways involved in Aβ -driven synaptic effects remain elusive. This review provides an overview of the mounting evidence showing Aβ -mediated effects on presynaptic functions and neurotransmitter release from axon terminals, focusing on its interaction with synaptic vesicle cycle. Indeed, Aβ peptides have …been found to interact with key presynaptic scaffold proteins and kinases affecting the consequential steps of the synaptic vesicle dynamics (e.g., synaptic vesicles exocytosis, endocytosis, and trafficking). Defects in the fine-tuning of synaptic vesicle cycle by Aβ and deregulation of key molecules and kinases, which orchestrate synaptic vesicle availability, may alter synaptic homeostasis, possibly contributing to synaptic loss and cognitive decline. Elucidating the presynaptic mechanisms by which Aβ regulate synaptic transmission is fundamental for a deeper comprehension of the biology of presynaptic terminals as well as of Aβ -driven early synaptic defects occurring in prodromal stage of AD. Moreover, a better understating of Aβ involvement in cellular signal pathways may allow to set up more effective therapeutic interventions by detecting relevant molecular mechanisms, whose imbalance might ultimately lead to synaptic impairment in AD. Show more

Keywords: Amyloid-β, intracellular signaling, neurotransmitter release, presynaptic function, SNARE complex, synaptic vesicle cycle

DOI: 10.3233/JAD-190771

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019