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Wai Hang Cheng, Kris M Martens, Asma Bashir, Honor Cheung, Sophie Stukas, Ebrima Gibbs, Dhananjay R Namjoshi, Emily B Button, Anna Wilkinson, Carlos J Barron, Neil R Cashman, Peter A Cripton, Cheryl L Wellington
BACKGROUND: The annual incidence of traumatic brain injury (TBI) in the United States is over 2.5 million, with approximately 3-5 million people living with chronic sequelae. Compared with moderate-severe TBI, the long-term effects of mild TBI (mTBI) are less understood but important to address, particularly for contact sport athletes and military personnel who have high mTBI exposure. The purpose of this study was to determine the behavioural and neuropathological phenotypes induced by the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model of mTBI in both wild-type (WT) and APP/PS1 mice up to 8 months post-injury...
January 12, 2019: Alzheimer's Research & Therapy
Andrew Octavian Sasmita
Alzheimer's disease (AD) is the most common form of dementia and has affected millions of individuals worldwide. The hallmarks of AD include the amyloid beta plaque deposits, tau neurofibrillary tangles, altered neuronal signaling, alongside decline in memory and cognitive functions. Conventional drug therapies do exist, such as donepezil or aducanumab, but these drugs mostly focus on halting AD progression instead of causing a reversal within the disease. In an effort to ameliorate and ultimately cure AD, researchers have delved into viral-mediated gene therapy to fix this disease from its root molecular causes...
October 14, 2018: Biotechnology & Genetic Engineering Reviews
Ping Chiao, Barry J Bedell, Brian Avants, Alex P Zijdenbos, Marilyn Grand'Maison, Paul O'Neill, John O'Gorman, Tianle Chen, Robert Koeppe
Standardized uptake value ratios (SUVRs) are commonly used to quantify tracer uptake in amyloid beta positron emission tomography (Aβ-PET). Here, we explore the impact of target and reference region of interest (ROI) selection on SUVR effect size using interventional data from the ongoing Phase Ib PRIME study (NCT01677572) of aducanumab (BIIB037) in patients with prodromal or mild Alzheimer's disease (AD). Methods: Florbetapir PET SUVR was calculated at baseline (screening) and Weeks 26 and 54 for patients randomized to placebo and each of four aducanumab doses (1, 3, 6, and 10 mg/kg), using whole cerebellum, cerebellar grey matter, cerebellar white matter, pons, and subcortical white matter as reference regions...
May 18, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Joseph W Arndt, Fang Qian, Benjamin A Smith, Chao Quan, Krishna Praneeth Kilambi, Martin W Bush, Thomas Walz, R Blake Pepinsky, Thierry Bussière, Stefan Hamann, Thomas O Cameron, Paul H Weinreb
Aducanumab, a human-derived antibody targeting amyloid-β (Aβ), is in Phase 3 clinical trials for the treatment of Alzheimer's disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3-7 of the Aβ peptide. Aducanumab discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates. Direct comparative studies with analogs of gantenerumab, bapineuzumab and solanezumab demonstrate clear differentiation in the binding properties of these antibodies...
April 23, 2018: Scientific Reports
Jia-Jie Mo, Jin-Yu Li, Zheng Yang, Zhou Liu, Jin-Shan Feng
To review the optimality and safety of different anti-Amyloid- β (Aβ) immunotherapies for Alzheimer's disease (AD). Published randomized controlled trials were comprehensively reviewed from electronic databases (Cochrane library, Embase, Pubmed, and Google scholar). Pooled outcomes as mean difference or odds ratio values with 95% confidence interval were reported. The network estimates with confidence and predictive intervals for all pairwise relative effects was evaluated. Optimal intervention was ranked by benefit-risk ratio based on the surface under the cumulative ranking curve...
December 2017: Annals of Clinical and Translational Neurology
S Budd Haeberlein, J O'Gorman, P Chiao, T Bussière, P von Rosenstiel, Y Tian, Y Zhu, C von Hehn, S Gheuens, L Skordos, T Chen, A Sandrock
The amyloid hypothesis has been the dominant framework for Alzheimer's disease (AD) research, including the development of anti-AD therapies. However, none of the phase III clinical trials conducted to date that targeted amyloid β (Aβ) production, aggregation, or clearance demonstrated a statistically significant treatment effect in patients with AD. This includes the approach of using monoclonal antibodies that recognize various Aβ epitopes and display different binding selectivity. While some monoclonal antibodies have failed in phase III trials, several are still in development...
2017: Journal of Prevention of Alzheimer's Disease
Youmei Wang, Tao Yan, Honghui Lu, Weiming Yin, Bin Lin, Weibin Fan, Xiaoli Zhang, Pedro Fernandez-Funez
BACKGROUND: Available drugs for the global Alzheimer disease (AD) epidemic only treat the symptoms without modifying disease progression. Accumulating evidence supports amyloid-β42 (Aβ42)as the key triggering agent in AD, making it the ideal target for disease-modifying therapies. Preclinical studies provided extensive support for passive Aβ42 immunotherapy, leading to human clinical trials with different antibodies. OBJECTIVE: Examine the status of clinical trials for passive immunotherapy against Aβ42...
2017: Neuro-degenerative Diseases
Jeff Sevigny, Ping Chiao, Thierry Bussière, Paul H Weinreb, Leslie Williams, Marcel Maier, Robert Dunstan, Stephen Salloway, Tianle Chen, Yan Ling, John O'Gorman, Fang Qian, Mahin Arastu, Mingwei Li, Sowmya Chollate, Melanie S Brennan, Omar Quintero-Monzon, Robert H Scannevin, H Moore Arnold, Thomas Engber, Kenneth Rhodes, James Ferrero, Yaming Hang, Alvydas Mikulskis, Jan Grimm, Christoph Hock, Roger M Nitsch, Alfred Sandrock
This corrects the article DOI: 10.1038/nature21361.
June 21, 2017: Nature
Kanchana K Gamage, Sushanth Kumar
No abstract text is available yet for this article.
April 26, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Thomas DiChiara, Nadia DiNunno, Jeffrey Clark, Riana Lo Bu, Erika N Cline, Madeline G Rollins, Yuesong Gong, David L Brody, Stephen G Sligar, Pauline T Velasco, Kirsten L Viola, William L Klein
Toxic amyloid beta oligomers (AβOs) are known to accumulate in Alzheimer's disease (AD) and in animal models of AD. Their structure is heterogeneous, and they are found in both intracellular and extracellular milieu. When given to CNS cultures or injected ICV into non-human primates and other non-transgenic animals, AβOs have been found to cause impaired synaptic plasticity, loss of memory function, tau hyperphosphorylation and tangle formation, synapse elimination, oxidative and ER stress, inflammatory microglial activation, and selective nerve cell death...
March 2017: Yale Journal of Biology and Medicine
Yu-Sung Cheng, Zih-Ten Chen, Tai-Yan Liao, Chen Lin, Howard C-H Shen, Ya-Han Wang, Chi-Wei Chang, Ren-Shyan Liu, Rita P-Y Chen, Pang-Hsien Tu
Alzheimer's disease (AD) is the most common neurodegenerative disease. Imbalance between the production and clearance of amyloid β (Aβ) peptides is considered to be the primary mechanism of AD pathogenesis. This amyloid hypothesis is supported by the recent success of the human anti-amyloid antibody aducanumab, in clearing plaque and slowing clinical impairment in prodromal or mild patients in a phase Ib trial. Here, a peptide combining polyarginines (polyR) (for charge repulsion) and a segment derived from the core region of Aβ amyloid (for sequence recognition) was designed...
May 2017: EMBO Molecular Medicine
Brian Murray, Bhanushee Sharma, Georges Belfort
Although the amyloid (abeta peptide, Aβ) hypothesis is 25 years old, is the dominant model of Alzheimer's disease (AD) pathogenesis, and guides the development of potential treatments, it is still controversial. One possible reason is a lack of a mechanistic path from the cleavage products of the amyloid precursor protein (APP) such as soluble Aβ monomer and soluble molecular fragments to the deleterious effects on synaptic form and function. From a review of the recent literature and our own published work including aggregation kinetics and structural morphology, Aβ clearance, molecular simulations, long-term potentiation measurements with inhibition binding, and the binding of a commercial monoclonal antibody, aducanumab, we hypothesize that the N-terminal domains of neurotoxic Aβ oligomers are implicated in causing the disease...
March 15, 2017: ACS Chemical Neuroscience
Ksenia V Kastanenka, Thierry Bussiere, Naomi Shakerdge, Fang Qian, Paul H Weinreb, Ken Rhodes, Brian J Bacskai
Calcium homeostasis plays a major role in maintaining neuronal function under physiological conditions. Amyloid-β (Aβ) initiates pathological processes that include disruption in intracellular calcium levels, so amelioration of the calcium alteration could serve as an indirect functional indicator of treatment efficacy. Therefore, calcium dynamics were used as a measure of functional outcome. We evaluated the effects of the anti-Aβ antibody aducanumab on calcium homeostasis and plaque clearance in aged Tg2576 mice with in vivo multiphoton imaging...
December 14, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Tara M Weitz, Terrence Town
In a recent issue of Nature, Sevigny et al. (2016) report findings from a phase 1b clinical trial of aducanumab (a monoclonal antibody targeting misfolded amyloid-β peptides), revitalizing the "amyloid cascade hypothesis" and bringing mononuclear phagocytes center stage in the treatment of Alzheimer's disease.
October 18, 2016: Immunity
David E Vaillancourt
No abstract text is available yet for this article.
November 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Francesco Panza, Davide Seripa, Vincenzo Solfrizzi, Bruno P Imbimbo, Madia Lozupone, Antonio Leo, Rodolfo Sardone, Gaetano Gagliardi, Lucia Lofano, Bianca C Creanza, Paola Bisceglia, Antonio Daniele, Antonello Bellomo, Antonio Greco, Giancarlo Logroscino
Currently available drugs against Alzheimer's disease (AD) target cholinergic and glutamatergic neurotransmissions without affecting the underlying disease process. Putative disease-modifying drugs are in development and target β-amyloid (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease. Areas covered: Phase III clinical studies of emerging anti-Aβ drugs for the treatment of AD were searched in US and EU clinical trial registries and in the medical literature until May 2016...
December 2016: Expert Opinion on Emerging Drugs
Jeff Sevigny, Ping Chiao, Thierry Bussière, Paul H Weinreb, Leslie Williams, Marcel Maier, Robert Dunstan, Stephen Salloway, Tianle Chen, Yan Ling, John O'Gorman, Fang Qian, Mahin Arastu, Mingwei Li, Sowmya Chollate, Melanie S Brennan, Omar Quintero-Monzon, Robert H Scannevin, H Moore Arnold, Thomas Engber, Kenneth Rhodes, James Ferrero, Yaming Hang, Alvydas Mikulskis, Jan Grimm, Christoph Hock, Roger M Nitsch, Alfred Sandrock
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner...
September 1, 2016: Nature
Robert Briggs, Sean P Kennelly, Desmond O'Neill
Despite the significant public health issue that it poses, only five medical treatments have been approved for Alzheimer's disease (AD) and these act to control symptoms rather than alter the course of the disease. Studies of potential disease-modifying therapy have generally been undertaken in patients with clinically detectable disease, yet evidence suggests that the pathological changes associated with AD begin several years before this. It is possible that pharmacological therapy may be beneficial in this pre-clinical stage before the neurodegenerative process is established...
June 2016: Clinical Medicine: Journal of the Royal College of Physicians of London
Fabrizio Piazza, Bengt Winblad
At the 8th International Conference on Clinical Trials in Alzheimer's Disease held November 5-7, 2015 in Barcelona, Spain, promising data were presented on two candidate Alzheimer's disease immunotherapeutic agents, gantenerumab and aducanumab. Trial results demonstrated that the implementation of cerebrospinal fluid and Aβ-PET biomarkers improves trial enrichment and outcome, which has led to a change in targeting strategy as clinical trials would be conducted with earlier, even presymptomatic, stages of the disease...
March 29, 2016: Journal of Alzheimer's Disease: JAD
Dennis J Selkoe, John Hardy
Despite continuing debate about the amyloid β-protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ...
June 2016: EMBO Molecular Medicine
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