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https://www.readbyqxmd.com/read/28817311/beta-secretase-inhibitors-in-phase-i-and-phase-ii-clinical-trials-for-alzheimer-s-disease
#1
Charbel E-H Moussa
BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-β peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aβ accumulation and halt AD onset and progression...
August 17, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28817283/the-effects-of-a21g-mutation-on-transmembrane-amyloid-beta-11-40-trimer-an-in-silico-study
#2
Son Tung Ngo, Minh Tung Nguyen, Nguyen Thanh Nguyen, Van V Vu
Familial Alzheimer's disease (FAD) is passed down in family, which account for 2-3% of about 40 million AD cases worldwide. The Flemish (A21G) mutant of amyloid β (Aβ) exhibits unique properties among all hereditary mutants of FAD, including lowest aggregation rate. Recent studies showed that Aβ oligomers play key role in Alzheimer's disease (AD) pathogenesis. They could insert themselves in brain cell membrane, disrupting the membrane integrity and ion homeostasis. However, experimental studies of transmembrane Aβ oligomers have been limited due to their intrinsic heterogeneity...
August 17, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28817221/neuroprotective-effects-of-honokiol-from-chemistry-to-medicine
#3
REVIEW
Sylwia Talarek, Joanna Listos, Davide Barreca, Ester Tellone, Antoni Sureda, Seyed Fazel Nabavi, Nady Braidy, Seyed Mohammad Nabavi
The incidence of neurological disorders is growing in developed countries together with increased lifespan. Nowadays, there are still no effective treatments for neurodegenerative pathologies, which make necessary to search for new therapeutic agents. Natural products, most of them used in traditional medicine, are considered promising alternatives for the treatment of neurodegenerative diseases. Honokiol is a natural bioactive phenylpropanoid compound, belonging to the class of neolignan, found in notable amounts in the bark of Magnolia tree, and has been reported to exert diverse pharmacological properties including neuroprotective activities...
August 17, 2017: BioFactors
https://www.readbyqxmd.com/read/28815875/the-pathogenic-a2v-mutant-exhibits-distinct-aggregation-kinetics-metal-site-structure-and-metal-exchange-of-the-cu2-a%C3%AE-complex
#4
Lars Hemmingsen, Arun K Somavarapu, Fei Shen, Kaare Teillum, Jingdong Zhang, Susanne Mossin, Peter W Thulstrup, Morten J Bjerrum, Manish K Tiwari, Daniel Szunyogh, Peter M Søfotfe, Kasper K Kepp
A prominent current hypothesis is that impaired metal ion homeostasis may contribute to Alzheimer's Disease (AD). We elucidate the interaction of Cu2+ with wild-type (WT) Aβ1-40 and the genetic variants A2T and A2V which display increasing pathogenicity as A2T<WT<A2V. Cu2+ significantly extends the lag phase in aggregation kinetics, in particular for the pathogenic A2V variant. Additionally, a rapid, initial, low intensity ThT response is observed, possibly reflecting formation of Cu2+ induced amorphous aggregates, as supported by AFM and CD spectroscopy, again most notably for the A2V variant...
August 16, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28814675/retinal-amyloid-pathology-and-proof-of-concept-imaging-trial-in-alzheimer-s-disease
#5
Yosef Koronyo, David Biggs, Ernesto Barron, David S Boyer, Joel A Pearlman, William J Au, Shawn J Kile, Austin Blanco, Dieu-Trang Fuchs, Adeel Ashfaq, Sally Frautschy, Gregory M Cole, Carol A Miller, David R Hinton, Steven R Verdooner, Keith L Black, Maya Koronyo-Hamaoui
BACKGROUND: Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits. METHODS: Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37)...
August 17, 2017: JCI Insight
https://www.readbyqxmd.com/read/28812046/extra-virgin-olive-oil-ameliorates-cognition-and-neuropathology-of-the-3xtg-mice-role-of-autophagy
#6
Elisabetta Lauretti, Luigi Iuliano, Domenico Praticò
OBJECTIVE: Consumption of extra virgin olive oil (EVOO), a major component of the Mediterranean diet, has been associated with reduced incidence of Alzheimer's disease (AD). However, the mechanisms involved in this protective action remain to be fully elucidated. METHODS: Herein, we investigated the effect of daily consumption of EVOO on the AD-like phenotype of a mouse mode of the disease with plaques and tangles. RESULTS: Triple transgenic mice (3xTg) received either regular chow or a chow diet supplemented with EVOO starting at 6 months of age for 6 months, then assessed for the effect of the diet on the AD-like neuropathology and behavioral changes...
August 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28811267/app-a%C3%AE-structural-diversity-and-alzheimer-s-disease-pathogenesis
#7
REVIEW
Alex E Roher, Tyler A Kokjohn, Steven G Clarke, Michael R Sierks, Chera L Maarouf, Geidy E Serrano, Marwan S Sabbagh, Thomas G Beach
The amyloid cascade hypothesis of Alzheimer's disease (AD) proposes amyloid- β (Aβ) is a chief pathological element of dementia. AD therapies have targeted monomeric and oligomeric Aβ 1-40 and 1-42 peptides. However, alternative APP proteolytic processing produces a complex roster of Aβ species. In addition, Aβ peptides are subject to extensive posttranslational modification (PTM). We propose that amplified production of some APP/Aβ species, perhaps exacerbated by differential gene expression and reduced peptide degradation, creates a diverse spectrum of modified species which disrupt brain homeostasis and accelerate AD neurodegeneration...
August 12, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28810189/hydroxy-substituted-trans-cinnamoyl-derivatives-as-multifunctional-tools-in-the-context-of-alzheimer-s-disease
#8
Angela De Simone, Manuela Bartolini, Andrea Baschieri, Kim Y P Apperley, Huan Huan Chen, Melissa Guardigni, Serena Montanari, Tereza Kobrlova, Ondrej Soukup, Luca Valgimigli, Vincenza Andrisano, Jeffrey W Keillor, Manuela Basso, Andrea Milelli
Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. In recent years, a plethora of proteins and biochemical pathways has been proposed as possible targets to counteract neurotoxicity. Although the complex scenario is not completely elucidated, close relationships are emerging among some of these actors. In particular, increasing evidence has shown that aggregation of amyloid beta (Aβ), glycogen synthase kinase 3β (GSK-3β) and oxidative stress are strictly interconnected and their concomitant modulation may have a positive and synergic effect in contrasting AD-related impairments...
July 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28808293/targeting-apolipoprotein-e-amyloid-%C3%AE-binding-by-peptoid-cpo_a%C3%AE-17-21%C3%A2-p-ameliorates-alzheimer-s-disease-related-pathology-and-cognitive-decline
#9
Shan Liu, Shinae Park, Grant Allington, Frances Prelli, Yanjie Sun, Mitchell Martá-Ariza, Henrieta Scholtzova, Goutam Biswas, Bernard Brown, Philip B Verghese, Pankaj D Mehta, Yong-Uk Kwon, Thomas Wisniewski
Inheritance of the apolipoprotein E4 (apoE4) genotype has been identified as the major genetic risk factor for late onset Alzheimer's disease (AD). Studies have shown that apoE, apoE4 in particular, binds to amyloid-β (Aβ) peptides at residues 12-28 of Aβ and this binding modulates Aβ accumulation and disease progression. We have previously shown in several AD transgenic mice lines that blocking the apoE/Aβ interaction with Aβ12-28 P reduced Aβ and tau-related pathology, leading to cognitive improvements in treated AD mice...
August 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808140/amyloid-%C3%AE-and-islet-amyloid-pathologies-link-alzheimer-disease-and-type-2-diabetes-in-a-transgenic-model
#10
Nadeeja Wijesekara, Rosemary Ahrens, Miheer Sabale, Ling Wu, Kathy Ha, Giuseppe Verdile, Paul E Fraser
Alzheimer's disease (AD) and type 2 diabetes (T2D) present a significant risk to each other. AD and T2D are characterized by deposition of cerebral amyloid-β (Aβ) and pancreatic human islet amyloid polypeptide (hIAPP), respectively. We investigated the role of amyloidogenic proteins in the interplay between these diseases. A novel double transgenic mouse model combining T2D and AD was generated and characterized. AD-related amyloid transgenic mice coexpressing hIAPP displayed peripheral insulin resistance, hyperglycemia, and glucose intolerance...
August 14, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28807816/mtor-in-down-syndrome-role-in-a%C3%A3-and-tau-neuropathology-and-transition-to-alzheimer-disease-like-dementia
#11
REVIEW
Fabio Di Domenico, Antonella Tramutola, Cesira Foppoli, Elisabeth Head, Marzia Perluigi, D Allan Butterfield
The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age-dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD-like dementia in Down syndrome (DS)...
August 11, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28806762/a-becn1-mutation-mediates-hyperactive-autophagic-sequestration-of-amyloid-oligomers-and-improved-cognition-in-alzheimer-s-disease
#12
Altea Rocchi, Soh Yamamoto, Tabitha Ting, Yuying Fan, Katherine Sadleir, Yigang Wang, Weiran Zhang, Sui Huang, Beth Levine, Robert Vassar, Congcong He
Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid β (Aβ) peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28804567/the-characteristics-of-astrocyte-on-a%C3%AE-clearance-altered-in-alzheimer-s-disease-were-reversed-by-anti-inflammatory-agent-2-1-hydroxyl-4-oxocyclohexyl-ethyl-caffeate
#13
Sanjaya Kuruppu, Niwanthi W Rajapakse, Helena C Parkington, A Ian Smith
No abstract text is available yet for this article.
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28803064/high-glucose-induces-tau-hyperphosphorylation-through-activation-of-tlr9-p38mapk-pathway
#14
Yue Sun, Qian Xiao, Cheng Luo, Yuxing Zhao, Die Pu, Kexiang Zhao, Jinliang Chen, Meili Wang, Zhiyin Liao
Diabetic encephalopathy (DE) is one of the most common complications of diabetes. The major pathological variations include neurofibrillary tangles (NFTs), which are caused by tau hyperphosphorylation, and senile plaques (SPs) consisting of amyloid β- protein(Aβ) deposits. In recent years, DE research studies have focused on exploring the activation of the inflammatory signaling pathway in immune cells. Toll-like receptor 9 (TLR9) is well known to regulate the inflammatory reactions in immune processes. During the tau hyperphosphorylation process, TLR9 in microglia plays bidirectional roles...
August 9, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28803044/new-racemic-annulated-pyrazolo-1-2-b-phthalazines-as-tacrine-like-ache-inhibitors-with-potential-use-in-alzheimer-s-disease
#15
Leili Jalili-Baleh, Hamid Nadri, Alireza Moradi, Syed Nasir Abbas Bukhari, Mojtaba Shakibaie, Mandana Jafari, Mostafa Golshani, Farshad Homayouni Moghadam, Loghman Firoozpour, Ali Asadipour, Saeed Emami, Mehdi Khoobi, Alireza Foroumadi
A novel series of tacrine-like compounds 7a-u possessing a fused pyrazolo[1,2-b]phthalazine structure were designed and synthesized as potent and selective inhibitors of AChE. The in-vitro biological assessments demonstrated that several compounds had high anti-AChE activity at nano-molar level. The more promising compound 7l with IC50 of 49 nM was 7-fold more potent than tacrine and unlike tacrine, it was highly selective against AChE over BuChE. The cell-based assays against hepatocytes (HepG2) and neuronal cell line (PC12) revealed that 7l had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H2O2-induced damage in PC12 cells...
July 31, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28802916/brain-region-and-sex-specific-alterations-in-mitochondrial-function-and-nf-%C3%AE%C2%BAb-signaling-in-the-tgcrnd8-mouse-model-of-alzheimer-s-disease
#16
Jelena Djordjevic, Ella Thomson, Subir Roy Chowdhury, Wanda M Snow, Claudia Perez, Tak Pan Wong, Paul Fernyhough, Benedict C Albensi
Alzheimer's disease (AD) is the most common late onset neurodegenerative disorder with indications that women are disproportionally affected. Mitochondrial dysfunction has been one of the most discussed hypotheses associated with the early onset and progression of AD, and it has been attributed to intraneuronal accumulation of amyloid β (Aβ). It was suggested that one of the possible mediators for Aβ-impaired mitochondrial function is the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB plays important roles in brain inflammation and antioxidant defense, as well as in the regulation of mitochondrial function, and studies have confirmed altered NF-κB signaling in AD brain...
August 9, 2017: Neuroscience
https://www.readbyqxmd.com/read/28801274/mannich-base-approach-to-5-methoxyisatin-3-4-isopropylphenyl-hydrazone-a-water-soluble-prodrug-for-a-multitarget-inhibition-of-cholinesterases-beta-amyloid-fibrillization-and-oligomer-induced-cytotoxicity
#17
Leonardo Pisani, Annalisa De Palma, Nicola Giangregorio, Daniela V Miniero, Paolo Pesce, Orazio Nicolotti, Francesco Campagna, Cosimo D Altomare, Marco Catto
Targeting protein aggregation for the therapy of neurodegenerative diseases remains elusive for medicinal chemists, despite a number of small molecules known to interfere in amyloidogenesis, particularly of amyloid beta (Aβ) protein. Starting from previous findings in the antiaggregating activity of a class of indolin-2-ones inhibiting Aβ fibrillization, 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone 1 was identified as a multitarget inhibitor of Aβ aggregation and cholinesterases with IC50s in the low μM range...
August 8, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28800459/novel-cinnamamide-dibenzylamine-hybrids-potent-neurogenic-agents-with-antioxidant-cholinergic-and-neuroprotective-properties-as-innovative-drugs-for-alzheimer-s-disease
#18
Jin Wang, Pei Cai, Xue-Lian Yang, Fan Li, Jia-Jia Wu, Ling-Yi Kong, Xiao-Bing Wang
By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced β-amyloid (Aβ) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE...
August 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28800330/pet-tau-and-amyloid-%C3%AE-burden-in-mild-alzheimer-s-disease-divergent-relationship-with-age-cognition-and-cerebrospinal-fluid-biomarkers
#19
Ivan Koychev, Roger N Gunn, Azadeh Firouzian, Jennifer Lawson, Giovanna Zamboni, Basil Ridha, Barbara J Sahakian, James B Rowe, Alan Thomas, Lynn Rochester, Dominic Ffytche, Robert Howard, Henrik Zetterberg, Clare MacKay, Simon Lovestone
BACKGROUND: Combining PET amyloid-β (Aβ) and tau imaging may be critical for tracking disease progression in Alzheimer's disease (AD). OBJECTIVE: We sought to characterize the relationship between Aβ and tau ligands as well as with other measures of pathology. METHODS: We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with Aβ ([18F]AV45) and tau ([18F]AV1451) ligands at baseline...
August 8, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28800329/chronic-verubecestat-treatment-suppresses-amyloid-accumulation-in-advanced-aged-tg2576-a%C3%AE-ppswe-mice-without-inducing-microhemorrhage
#20
Stephanie Villarreal, Fuqiang Zhao, Lynn A Hyde, Daniel Holder, Thomas Forest, Marie Sondey, Xia Chen, Cyrille Sur, Eric M Parker, Matthew E Kennedy
Verubecestat is a potent BACE1 enzyme inhibitor currently being investigated in Phase III trials for the treatment of mild-to-moderate and prodromal Alzheimer's disease. Multiple anti-amyloid immunotherapies have been dose-limited by adverse amyloid related imaging abnormalities such as vasogenic edema (ARIA-E) and microhemorrhage (ARIA-H) observed in human trials and mice. Verubecestat was tested in a 12-week nonclinical study for the potential to exacerbate microhemorrhage (ARIA-H) profiles in 18-22-month-old post-plaque Tg2576-AβPPswe mice...
August 8, 2017: Journal of Alzheimer's Disease: JAD
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