Journal of Alzheimer's Disease - Volume 67, issue 3

Authors: Ashford, John Wesson

Article Type: Article Commentary

Abstract: In this issue, an article by La et al. provides evidence that trazodone delayed cognitive decline in 25 participants with Alzheimer’s disease (AD), mild cognitive impairment, or normal cognition. For participants considered to have AD pathology, trazodone non-users declined at a rate 2.4 times greater than those taking trazodone for sleep over a 4-year period. In the analysis of sleep complaints, the relationship between trazodone, a widely used medication for sleep problems in the elderly, and cognition was associated with subjective improvement of sleep disruption. Due to the design of the study, it was not possible to prove that the …benefit of slowing cognitive decline was due specifically to the improvement in sleep. However, trazodone uniquely improves the deeper phases of slow-wave sleep. Other sedative medications are generally associated with worse cognitive function over time, and they do not improve sleep characteristics as does trazodone. Trazodone has a variety of effects on several monoaminergic mechanisms: a potent serotonin 5-HT2A and α 1-adrenergic receptor antagonist, a weak serotonin reuptake inhibitor, and a weak antihistamine or histamine H1 receptor inverse agonist. Because of the potential importance of this finding, further discussion is provided on the roles that trazodone may play in the modulation of monoamines, cognition, and the development of AD. If trazodone really does provide such a dramatic slowing in the development of dementia associated with AD, a great deal more research on trazodone is needed, including environmental and behavioral factors related to improvement of sleep, energy management, and neuroplasticity. Show more

Keywords: Alzheimer’s disease, energy, neuroplasticity, norepinephrine, serotonin, sleep, trazodone, treatment

DOI: 10.3233/JAD-181106

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 923-930, 2019

Authors: Hudd, Fred | Shiel, Anna | Harris, Matthew | Bowdler, Paul | McCann, Bryony | Tsivos, Demitra | Wearn, Alfie | Knight, Michael | Kauppinen, Risto | Coulthard, Elizabeth | White, Paul | Conway, Myra Elizabeth

Article Type: Research Article

Abstract: Background: Differential diagnosis of people presenting with mild cognitive impairment (MCI) that will progress to Alzheimer’s disease (AD) remains clinically challenging. Current criteria used to define AD include a series of neuropsychological assessments together with relevant imaging analysis such as magnetic resonance imaging (MRI). The clinical sensitivity and specificity of these assessments would be improved by the concomitant use of novel serum biomarkers. The branched chain aminotransferase proteins (BCAT) are potential candidates as they are significantly elevated in AD brain, correlate with Braak Stage, and may have a role in AD pathology. Objective: In this hypothesis-driven project, we …aimed to establish if serum BCAT and its metabolites are significantly altered in AD participants and assess their role as markers of disease pathology. Methods: Serum amino acids were measured using a triple quadrupole mass spectrometer for tandem mass spectroscopy together with BCAT levels using western blot analysis, coupled with neuropsychological assessments and MRI. Results: We present data supporting a substantive mutually correlated system between BCAT and glutamate, neuropsychological tests, and MRI for the diagnosis of AD. These three domains, individually, and in combination, show good utility in discriminating between groups. Our model indicates that BCAT and glutamate accurately distinguish between control and AD participants and in combination with the neuropsychological assessment, MoCA, improved the overall sensitivity to 1.00 and specificity to 0.978. Conclusion: These findings indicate that BCAT and glutamate have potential to improve the clinical utility and predictive power of existing methods of AD assessment and hold promise as early indicators of disease pathology. Show more

Keywords: Alzheimer’s disease, BCAT, biomarkers, cognitive assessment, glutamate

DOI: 10.3233/JAD-180879

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 931-947, 2019

Authors: Kristensen, Rachel Underlien | Nørgaard, Ane | Jensen-Dahm, Christina | Gasse, Christiane | Wimberley, Theresa | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Polypharmacy, the use of multiple medications, has become increasingly widespread. Information on time trends in polypharmacy in people with dementia is limited, although they may be more susceptible to risks associated with polypharmacy. Objective: To examine changes in the prevalence of polypharmacy and excessive polypharmacy in people with dementia compared to changes in people without dementia. Methods: Repeated cross-sectional study of the entire Danish population aged≥65 from 2000 (n  = 790,717) to 2014 (n  = 1,028,377) using linked register data on diagnoses, filled prescriptions, and demographic data. Multivariate analyses were performed to explore changes in the prevalence …of polypharmacy and excessive polypharmacy (≥5 and≥10 different prescription drugs). This was done before and after 2011 to examine whether increasing awareness of potential problems associated with polypharmacy has altered the trend. Estimates for people with and without dementia were compared. Results: In people with dementia, the prevalence of polypharmacy increased from 47.3% to 69.4% from 2000 to 2011 and excessive polypharmacy from 7.4% to 20.9%. In people without dementia, polypharmacy increased from 22.7% to 36.1% and excessive polypharmacy from 3.5% to 7.7%. The increase was significantly more marked in people with dementia across all age groups. From 2011 to 2014, the prevalence of polypharmacy and excessive polypharmacy remained relatively stable: Polypharmacy decreased negligibly from 69.4% to 68.1% in people with dementia and from 36.1% to 35.2% in people without dementia. Conclusion: Although the increasing trend has halted, polypharmacy remains widespread in people with dementia. Further research is needed to explore possible implications. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, polypharmacy

DOI: 10.3233/JAD-180427

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 949-960, 2019

Authors: Wang, Qing | Zhou, Wenjun | Zhang, Jie | for Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Although a growing body of evidence shows an important role of apolipoproteins in the pathogenesis of Alzheimer’s disease (AD), the association of apolipoprotein C-III (APOC-III) with cognitive decline is not clear. Objective: To examine whether higher cerebrospinal fluid (CSF) and plasma APOC-III levels were associated with better cognitive performance over time in the early stage of AD. Methods: Baseline CSF and plasma APOC-III levels were analyzed in relation to cross-sectionally and longitudinally cognitive performance over a 12-year period. Data were extracted from the Alzheimer’s Disease Neuroimaging Initiative database, and 234 subjects (89 subjects with normal …cognition (NC) and 145 subjects with mild cognitive impairment (MCI)) with CSF APOC-III measurements and 454 subjects (58 subjects with NC and 396 subjects with MCI) with plasma APOC-III measurements were included. Results: In the cross-sectional study, we did not find a significant relationship between CSF APOC-III and cognitive performance in pooled individuals with MCI and NC. However, longitudinal analysis found that higher baseline CSF APOC-III was significantly associated with slower cognitive decline over a 12-year period in individuals with MCI, but not the healthy controls, after controlling for several covariates and Alzheimer biomarkers. Plasma APOC-III levels showed a mild correlation with CSF APOC-III levels, but were not associated with longitudinal cognitive changes in the pooled sample or in diagnosis-stratified analyses. Conclusions: Higher CSF APOC-III levels are significantly associated with slower cognitive decline over a 12-year period among individuals with MCI. Show more

Keywords: Alzheimer’s disease, apolipoprotein C-III, cognitive decline, mild cognitive impairment

DOI: 10.3233/JAD-181096

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 961-969, 2019

Authors: Klobušiaková, Patrícia | Mareček, Radek | Fousek, Jan | Výtvarová, Eva | Rektorová, Irena

Article Type: Research Article

Abstract: Background: Cognitive impairment in Parkinson’s disease (PD) is associated with altered connectivity of the resting state networks (RSNs). Longitudinal studies in well cognitively characterized PD subgroups are missing. Objectives: To assess changes of the whole-brain connectivity and between-network connectivity (BNC) of large-scale functional networks related to cognition in well characterized PD patients using a longitudinal study design and various analytical methods. Methods: We explored the whole-brain connectivity and BNC of the frontoparietal control network (FPCN) and the default mode, dorsal attention, and visual networks in PD with normal cognition (PD-NC, n  = 17) and mild cognitive impairment …(PD-MCI, n  = 22) as compared to 51 healthy controls (HC). We applied regions of interest-based, partial least squares, and graph theory based network analyses. The differences among groups were analyzed at baseline and at the one-year follow-up visit (37 HC, 23 PD all). Results: The BNC of the FPCN and other RSNs was reduced, and the whole-brain analysis revealed increased characteristic path length and decreased average node strength, clustering coefficient, and global efficiency in PD-NC compared to HC. Values of all measures in PD-MCI were between that of HC and PD-NC. After one year, the BNC was further increased in the PD-all group; no changes were detected in HC. No cognitive domain z-scores deteriorated in either group. Conclusion: As compared to HC, PD-NC patients display a less efficient transfer of information globally and reduced BNC of the visual and frontoparietal control network. The BNC increases with time and MCI status, reflecting compensatory efforts. Show more

Keywords: Between-network connectivity, cognitive resting state brain networks, functional MRI, graph measures, longitudinal, mild cognitive impairment, Parkinson’s disease, partial least squares analysis

DOI: 10.3233/JAD-180834

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 971-984, 2019

Authors: Gallucci, Maurizio | Dell’Acqua, Carola | Bergamelli, Cristina | Fenoglio, Chiara | Serpente, Maria | Galimberti, Daniela | Fiore, Vittorio | Medea, Stefano | Gregianin, Michele | Di Battista, Maria Elena

Article Type: Research Article

Abstract: We report the case of a woman firstly referred to our Memory Clinic at the age of 61, following the development of cognitive complaints and difficulties in sustained attention. The investigation that was performed showed: predominant executive dysfunctions at the neuropsychological evaluation, with mild, partial and stable involvement of the memory domain; cortical and subcortical atrophy with well-preserved hippocampal structures at MRI; marked fronto-temporal and moderate parietal hypometabolism from 18 F-FDG PET study with a sparing of the posterior cingulate and precuneus; positivity of amyloid-β at 18 F-Flutemetamol PET; an hexanucleotide intermediate repeats expansion of C9ORF72 gene (12//38 repeats) …and ApoE genotype ɛ 4/ɛ 4. The patient was diagnosed with probable early onset frontal variant of Alzheimer’s disease (AD), presenting with a major executive function impairment. The lack of specific areas of brain atrophy, as well as the failure to meet the clinical criteria for any frontotemporal dementia, drove us to perform the aforementioned investigations, which yielded our final diagnosis. The present case highlights the need to take into consideration a diagnosis of frontal variant of AD when the metabolic and the clinical picture are somehow dissonant. Show more

Keywords: ApoE, C9ORF72 HREs, early onset Alzheimer’s disease, FDG PET, TREDEM Registry

DOI: 10.3233/JAD-180715

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 985-993, 2019

Authors: Moylett, Sinéad | Price, Annabel | Cardinal, Rudolf N. | Aarsland, Dag | Mueller, Christoph | Stewart, Rob | O’Brien, John T.

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) is the second most common degenerative dementia in older people. However, rates of misdiagnosis are high, and little is known of its natural history and outcomes. Very few previous studies have been able to access routine clinical information for large, unbiased DLB cohorts in order to establish initial presentation, neuropsychological profile, and mortality. Objective: To examine in detail, symptom patterns at presentation and their association with outcomes, including mortality, in a large naturalistic DLB cohort from a secondary care sample. Methods: A retrospective cohort design was used to identify a …DLB cohort (n = 251) from Cambridgeshire and Peterborough NHS Foundation Trust (CPFT). Information relating to first consultation, diagnosis, and DLB diagnostic features were extracted. Results: A wide range of presenting complaints and differential initial diagnoses were identified for the cohort. Along with memory loss (27.1%) and hallucinations (25.4%), low mood (25.1%) was noted as a key presenting complaint among the DLB cohort. Rates of REM sleep disorder were considerably lower (8.4%) than would be expected. Deficits in non-amnestic cognitive domains were associated with reduced mortality compared with amnestic-only presentations. Conclusion: Individuals later diagnosed with DLB present initially to secondary care with a wide range of symptoms and complaints, some of which are not immediately suggestive of a DLB diagnosis. More examinations of large cohorts such as this are needed to further elucidate the complex presentation and clinical course of DLB, and to confirm whether amnestic-only presentation confers a worse outcome. Show more

Keywords: Clinical presentation, Dementia with Lewy bodies, diagnostic features, mortality, retrospective cohort

DOI: 10.3233/JAD-180877

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 995-1005, 2019

Authors: Ding, Yanfei | Bao, Xiaoming | Lao, Lifeng | Ling, Yunxiang | Wang, Qinwen | Xu, Shujun

Article Type: Research Article

Abstract: p-hydroxybenzyl alcohol (HBA) is one of the major components of Gastrodia elata Blume (GEB) phenolic compound. HBA has been reported to have a protective effect on amyloid-β (Aβ) induced cell death. However, the systemic effects and the detail molecular mechanism of HBA in Alzheimer’s disease (AD) animal models is not clear. In this study, we revealed the protective effects and the potential mechanisms of HBA on the impairments of cognitive function induced by soluble Aβ oligomers. Our results showed that HBA prevented neuronal cells death in a dose-dependent manner. The working memory and the spatial memory were significantly lower in …AD model mice. HBA treatment prevented the memory deficits of the AD mice. HBA treatment significantly prevented the decreased spine density and decreased expression levels of synaptic proteins induced by Aβ42 . In addition, both mRNA levels and protein levels of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in the Aβ42 -treated mice were decreased, the decreases were prevented by HBA treatment. The expression levels of TNF-α and IL-1β were increased by Aβ42 treatment and the increase can be prevented by the HBA treatment. Moreover, HBA prevents the decreases in the level of nuclear erythroid 2 p45-related factor 2 (Nrf2) induced by Aβ42 in hippocampal. Thus, we predict that HBA might prevent Aβ42 oligomer-induced synapse and cognitive impairments through multiple targets including increasing Nrf2, increasing neurotrophic factors and decreasing inflammatory factors. Our study provided novel insights into the cellular mechanisms for the protective effects of HBA on AD. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, inflammatory factors, memory deficits, nuclear erythroid 2 p45-related factor 2, p-hydroxybenzyl alcohol

DOI: 10.3233/JAD-180910

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1007-1019, 2019

Authors: Ji, Yan | Wang, Xiaowan | Kalicki, Colin | Menta, Blaise W. | Baumgardner, Megan | Koppel, Scott J. | Weidling, Ian W. | Perez-Ortiz, Judit | Wilkins, Heather M. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Recent association studies indicate several genes highly expressed by microglia influence Alzheimer’s disease (AD) risk, which suggests microglial function contributes to this disease. Here, we evaluated how one component of microglial function, cytokine release, affects AD-related phenomena. First, we used a 3-hour lipopolysaccharide (LPS) treatment to activate mouse BV2 microglial cells. Next, we removed the LPS-containing medium, added LPS-free medium, and after 6 hours collected the medium conditioned by the activated BV2 microglial cells. We then exposed human neuronal SH-SY5Y cells to the conditioned medium for 24 hours. At the end of the 24-hour exposure, we assessed amyloid-β protein precursor …(AβPP), tau, apolipoprotein E (ApoE), and lipid status. The amount of AβPP was unaffected, although a slight decrease in soluble AβPPα suggested a subtle reduction in AβPP non-amyloidogenic processing occurred. Tau mRNA increased, but total and phosphorylated tau levels were unchanged. ApoE mRNA increased, while ApoE protein levels were lower. Per cell lipid droplet number decreased and lipid oxidation increased. These results show cytokine release by activated microglial cells can influence specific AD-relevant physiologies and pathologies. Show more

Keywords: Alzheimer’s disease, ApoE, inflammation, lipid droplets, microglia

DOI: 10.3233/JAD-180820

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1021-1034, 2019

Authors: Unsworth, Carolyn A. | Russell, Kay | Lovell, Robin | Woodward, Michael | Browne, Matthew

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease may be required to undertake clinical and on–road assessments to determine fitness to drive. The manner in which on–road assessments are conducted with drivers who do and do not have navigational problems may affect the outcome. Objectives: Investigate the effect of 1) navigational difficulties, 2) location of assessment (un/familiar area) and assessment order, and 3) undertaking a second assessment (practice), on passing an on–road driving assessment. Methods: Forty-three drivers undertook an Occupational Therapy-Driver Assessment Off Road Assessment (OT-DORA) Battery which included the Drive Home Maze Test (DHMT). Participants with/without a history …of navigational problems were randomly allocated into three groups: 1) Unfamiliar/then familiar area assessment; 2) Unfamiliar/unfamiliar; 3) familiar/unfamiliar. An on–road assessment protocol was used including over 100 expected behaviors at nominated points along the directed route. For familiar area assessments, the driver self-navigated from their home to shops and services. A pass/fail decision was made for each assessment. Results: A generalized linear mixed effects model showed neither location, nor practice affected passing the on–road assessment. Participants with navigational problems were six times less likely to pass regardless of route familiarity and direction method, and the DHMT was a significant negative predictor of passing. Conclusion: Drivers with Alzheimer’s disease who have navigational problems and are slow to complete the DHMT are unlikely to pass an on–road assessment. However, navigation and maze completion skills may be a proxy for an underlying cognitive skill underpinning driving performance. Show more

Keywords: Alzheimer’s disease, automobile driver examination, automobile driving, occupational therapy

DOI: 10.3233/JAD-181069

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1035-1043, 2019

Authors: van der Hoek, Marjanne D. | Nieuwenhuizen, Arie | Keijer, Jaap | Ashford, J. Wesson

Article Type: Research Article

Abstract: Cognitive impairment is a leading cause of dysfunction in the elderly. When mild cognitive impairment (MCI) occurs in elderly, it is frequently a prodromal condition to dementia. The Montreal Cognitive Assessment (MoCA) is a commonly used tool to screen for MCI. However, this test requires a face-to-face administration and is composed of an assortment of questions whose responses are added together by the rater to provide a score whose precise meaning has been controversial. This study was designed to evaluate the performance of a computerized memory test (MemTrax), which is an adaptation of a continuous recognition task, with respect to …the MoCA. Two outcome measures are generated from the MemTrax test: MemTraxspeed and MemTraxcorrect . Subjects were administered the MoCA and the MemTrax test. Based on the results of the MoCA, subjects were divided in two groups of cognitive status: normal cognition (n = 45) and MCI (n = 37). Mean MemTrax scores were significantly lower in the MCI than in the normal cognition group. All MemTrax outcome variables were positively associated with the MoCA. Two methods, computing the average MTX score and linear regression were used to estimate the cutoff values of the MemTrax test to detect MCI. These methods showed that for the outcome MemTraxspeed a score below the range of 0.87 – 91 s-1 is an indication of MCI, and for the outcome MemTraxcorrect a score below the range of 85 – 90% is an indication for MCI. Show more

Keywords: Alzheimer’s disease, continuous performance task, dementia, elderly, memory, mild cognitive impairment, screening

DOI: 10.3233/JAD-181003

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1045-1054, 2019

Authors: Möllers, Tobias | Perna, Laura | Ihle, Peter | Schubert, Ingrid | Bauer, Jürgen | Brenner, Hermann

Article Type: Research Article

Abstract: BACKGROUND: Hospital care of older adults, especially of those with dementia, is associated with a high risk of complications and increased mortality. Adverse events are often triggered by hospital-related factors, hence the time spent in hospitals should be limited. There is little knowledge of the specific factors influencing hospitalizations of older persons. OBJECTIVES: To assess the duration of length of stay (LOS) and risk factors of increased LOS, and, specifically, the role of delirium and neuropsychiatric symptoms (NPS) among a large sample of older adults with and without dementia in Germany. METHODS: A claims data based …dynamic retrospective cohort study from 2004 to 2015 was conducted. People with dementia (PWD) were identified using ICD-10 codes and the application of diagnostic measures. A control group without diagnosis of dementia (CG) were matched in a 3: 1 ratio. Multivariate methods were used to investigate the factors associated with LOS. RESULTS: 7,139 PWD and 21,417 controls were included. PWD had longer hospitalizations (first LOS: +4.3 days; second LOS: +0.2 days) than the CG. Diagnosis of delirium was associated with LOS, both for PWD (first LOS: +9.6 days; second LOS: +5.3 days) and CG (first LOS: +13.7 days; second LOS: +7.2 days). CONCLUSION: Major determinants of LOS were similar in PWD and the CG. The strongest association was found for the presence of delirium and NPS. Future research should focus on prevention and intervention strategies that may reduce the impact of delirium as well as NPS on the length of stay especially for PWD. Show more

Keywords: Claims data, dementia, hospitalization, neuropsychiatric symptoms, observational study

DOI: 10.3233/JAD-180593

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1055-1065, 2019

Authors: Deng, Jing-Huan | Huang, Kai-Yong | Hu, Xiao-Xiao | Huang, Xiao-Wei | Tang, Xian-Yan | Wei, Xiao | Feng, Lei | Lu, Guo-Dong

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI), as a transitional stage between normal aging and dementia, causes cognitive decline among one-fifth of elders aged 65 years and older. Health-related lifestyles (HRL) are generally regarded as modifiable influencing factors of cognitive decline. The present study investigated how HRLs at two different life stages (one at midlife and the other at later life) affect MCI occurrence among community-dwelling elders, as part of the Diet and Healthy Aging (DaHA) study in Singapore. The frequencies of major HRL activities were compared between 119 clinical diagnosed MCI cases and 632 normal aging controls with functional cognition. The associations …of HRLs with MCI were determined by multivariate logistic regression analysis and adjusted according to known factors including age, childhood education, and major chronic diseases (hypertension, stroke, diabetes, and cataracts or glaucoma). Long-hour working in midlife (adjusted OR = 0.418 with 95% CI 0.215–0.812) and social engagement in later-life (adjusted OR = 0.532 with 95% CI 0.329–0.859) were associated with reduced risks of MCI, respectively. It is important to note that those elders who had both midlife long-hour working and later-life social engagement were related to the lowest risk of MCI (adjusted OR = 0.285 with 95% CI 0.143-0.565), when compared to the least active subgroup who neither had worked long hours in midlife nor participate in social activities in later-life. Therefore, the present study demonstrated that midlife long-hour working and later-life social engagement were modifiable factors for the maintenance of cognitive functions. Show more

Keywords: Health-related lifestyle, later-life, midlife, mild cognitive impairment, social engagement, work

DOI: 10.3233/JAD-180605

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1067-1077, 2019

Authors: Manabe, Tatsuo | Matsumura, Akihiro | Yokokawa, Kazuki | Saito, Taro | Fujikura, Mai | Iwahara, Naotoshi | Matsushita, Takashi | Suzuki, Syuuichirou | Hisahara, Shin | Kawamata, Jun | Suzuki, Hiromi | Emoto, Miho C. | Fujii, Hirotada G. | Shimohama, Shun

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases responsible for progressive dementia. Deposition of amyloid-β (Aβ) in the brain is the most important pathophysiological hallmark of AD. In addition, recent evidence indicates that reactive oxygen species (ROS) derived from mitochondria contribute to progression of AD pathology. We thus hypothesized that Aβ accumulates and oxidative stress increases in the brain mitochondria of a transgenic mouse model of AD (APdE9). We measured the quantity of Aβ and the activity of the antioxidant enzyme superoxide dismutase (SOD) in brain mitochondrial fractions prepared from APdE9 and wild-type (WT) mice aged 6, …9, 15, and 18 months. We also quantified the age-related changes in redox status in the mitochondrial fractions obtained from both APdE9 and WT mouse brains by electron paramagnetic resonance (EPR) spectrometry using a paramagnetic nitroxide “Mito-Tempo” [(2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride monohydrate] as a mitochondria-targeted redox-sensitive probe. In APdE9 mice, Aβ accumulated in brain mitochondria earlier than in the non-mitochondrial fraction of the brain. Furthermore, increased oxidative stress was demonstrated in brain mitochondria of APdE9 mice by in vitro SOD assay as well as EPR spectroscopy. EPR combined with a mitochondria-targeted redox-sensitive nitroxide probe is a potentially powerful tool to elucidate the etiology of AD and facilitate the development of new therapeutic strategies for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, electron paramagnetic resonance, mitochondria, reactive oxygen special, redox status, oxidative stress

DOI: 10.3233/JAD-180985

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1079-1087, 2019

Authors: Chen, Ci-Di | Zeldich, Ella | Khodr, Christina | Camara, Kaddy | Tung, Tze Yu | Lauder, Emma C. | Mullen, Patrick | Polanco, Taryn J. | Liu, Yen-Yu | Zeldich, Dean | Xia, Weiming | Van Nostrand, William E. | Brown, Lauren E. | Porco Jr., John A. | Abraham, Carmela R.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput screen of a compound library for inhibitors of AβPP dimerization, and identified a compound that reduces Aβ levels. In the present study, we have identified an analog, compound Y10, which also reduced Aβ. Initial kinase profiling assays …identified the receptor tyrosine kinase cKit as a putative Y10 target. To elucidate the precise mechanism involved, AβPP phosphorylation was examined by IP-western blotting. We found that Y10 inhibits cKit phosphorylation and increases AβPP phosphorylation mainly on tyrosine residue Y743, according to AβPP751 numbering. A known cKit inhibitor and siRNA specific to cKit were also found to increase AβPP phosphorylation and lower Aβ levels. We also investigated a cKit downstream signaling molecule, the Shp2 phosphatase, and found that known Shp2 inhibitors and siRNA specific to Shp2 also increase AβPP phosphorylation, suggesting that the cKit signaling pathway is also involved in AβPP phosphorylation and Aβ production. We further found that inhibitors of both cKit and Shp2 enhance AβPP surface localization. Thus, regulation of AβPP phosphorylation by small molecules should be considered as a novel therapeutic intervention for AD. Show more

Keywords: High throughput screening, kinase, neurodegeneration, phosphatase, phosphorylation

DOI: 10.3233/JAD-180923

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1089-1106, 2019

Article Type: Correction

DOI: 10.3233/JAD-189014

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 1107-1107, 2019