Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

Sevigny, Jeff; Chiao, Ping; Bussière, Thierry; Weinreb, Paul H.; Williams, Leslie; Maier, Marcel; Dunstan, Robert W.; Salloway, Stephen; Chen, Tianle; Ling, Yan; O’Gorman, John; Qian, Fang; Arastu, Mahin; Li, Mingwei; Chollate, Sowmya; Brennan, Melanie S.; Quintero-Monzon, Omar; Scannevin, Robert H.; Arnold, H. Moore; Engber, Thomas M.; Rhodes, Kenneth J.; Ferrero, James L.; Hang, Yaming; Mikulskis, Alvydas; Grimm, Jan; Höck, Christoph; Nitsch, Roger M.; Sandrock, Alfred

doi:10.1038/nature22809

Cited by 70 publications

(52 citation statements)

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“…This means that accumulation of Aβ might sequester Fe 2+ and contribute to a cytosolic deficiency, and is consistent with Aβ’s speculated antibacterial role (see later). Indeed, this might explain why one candidate anti-Aβ therapy has been seen to have ameliorative effects (even if somewhat minor) on Alzheimer’s disease progression in a phase 1b clinical trial ( Sevigny et al, 2016 , 2017 ).…”

Section: The Cytosolic Labile Iron Pool Ferritin and Autophagymentioning

confidence: 99%

Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

et al. 2018

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The overwhelming majority of dominant mutations causing early onset familial Alzheimer’s disease (EOfAD) occur in only three genes, PSEN1, PSEN2, and APP. An effect-in-common of these mutations is alteration of production of the APP-derived peptide, amyloid β (Aβ). It is this key fact that underlies the authority of the Amyloid Hypothesis that has informed Alzheimer’s disease research for over two decades. Any challenge to this authority must offer an alternative explanation for the relationship between the PSEN genes and APP. In this paper, we explore one possible alternative relationship – the dysregulation of cellular iron homeostasis as a common effect of EOfAD mutations in these genes. This idea is attractive since it provides clear connections between EOfAD mutations and major characteristics of Alzheimer’s disease such as dysfunctional mitochondria, vascular risk factors/hypoxia, energy metabolism, and inflammation. We combine our ideas with observations by others to describe a “Stress Threshold Change of State” model of Alzheimer’s disease that may begin to explain the existence of both EOfAD and late onset sporadic (LOsAD) forms of the disease. Directing research to investigate the role of dysregulation of iron homeostasis in EOfAD may be a profitable way forward in our struggle to understand this form of dementia.

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Section: The Cytosolic Labile Iron Pool Ferritin and Autophagymentioning

confidence: 99%

Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

et al. 2018

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“…AD is characterized by neurofibrillary tangles, synaptic dysfunction and neurodegeneration; its incidence is increasing rapidly with the aging of the population as an increasing number of individuals approach the key risk period for this age-related disease ( 26 , 27 ). Its characteristics include the loss of synapses and neuronal death, neurofibrillary tangles and extracellular Aβ plaques in the intracellular environment, all leading to cognitive decline ( 28 ).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

2018

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease that often occurs at a slow pace yet deteriorates with time. MicroRNAs (miRs) have been demonstrated to offer novel therapeutic hope for disease treatment. The aim of the present study was to investigate the effect of miR-98 on amyloid β (Aβ)-protein production, oxidative stress and mitochondrial dysfunction through the Notch signaling pathway by targeting hairy and enhancer of split (Hes)-related with YRPW motif protein 2 (HEY2) in mice with AD. A total of 70 Kunming mice were obtained and subjected to behavioral assessment. The levels of oxidative stress-related proteins glutathione peroxidase, reduced glutathione, super-oxide dismutase, malondialdehyde, acetylcholinesterase and Na+-K+-ATP were measured. Morphological changes in brain tissue, HEY2-positivity levels, neuronal apoptotic index (AI) and neuron mitochondrial DNA (mtDNA) levels were also determined. Subsequently, the levels of miR-98 and the mRNA and protein levels of HEY2, Jagged1, Notch1, Hes1, Hes5, β-amyloid precursor protein, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein in tissues and hippocampal neurons were determined by reverse transcription-quantitative polymerase chain reaction and western blot analyses, respectively. Finally, hippocampal neuron viability and apoptosis were determined using an MTT assay and flow cytometry, respectively. The levels of miR-98-targeted HEY2 and miR-98 were low and the levels of HEY2 were high in the AD mice. The AD mice exhibited poorer learning and memory abilities, oxidative stress function, and morphological changes of pyramidal cells in the hippocampal CA1 region. Furthermore, the AD mice exhibited increased protein levels of HEY2 and AI in the CA1 region of brain tissues with reduced mtDNA levels and dysfunctional neuronal mitochondria. miR-98 suppressed hippocampal neuron apoptosis and promoted hippocampal neuron viability by inactivating the Notch signaling pathway via the inhibition of HEY2. In conclusion, the results demonstrated that miR-98 reduced the production of Aβ and improved oxidative stress and mitochondrial dysfunction through activation of the Notch signaling pathway by binding to HEY2 in AD mice.

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“…Aducanumab has >10,000-fold increased selectivity for aggregated Ab species compared to monomers. 43,44 Crystal structures of the Fab revealed that the antibody binds residues 3-7 in an extended conformation, with Phe4 and His6 being critical to binding. 45 Biochemical analyses showed that weak binding affinity to Ab monomers, coupled with fast dissociation, contributed to high selectivity for aggregated species.…”

Section: Crenezumabmentioning

confidence: 99%

Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer’s Disease

Zanden

2020

Journal of Pharmaceutical Sciences

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Keywords:amyloid beta tau Alzheimer's disease protein oligomers passive immunotherapy protein aggregation protein structure blood brain barrier clearance CNS a b s t r a c t Alzheimer's disease (AD) is historically difficult to treat, in part because of the inaccessible nature of brain pathology. Amyloid beta and tau proteins drive pathology by forming toxic oligomers that eventually deposit as insoluble amyloid plaques and neurofibrillary tangles. Recent clinical studies suggest that effective drugs must specifically target oligomers, not native monomers or insoluble fibrils. Passive immunotherapy is a promising pharmaceutical strategy used to specifically target these oligomers in situ. Using the specificity of antibodies coupled with the natural power of the body's immune response, this treatment provides an opportunity for safe clearance of pathogenic protein species from the brain. Passive immunotherapies against amyloid beta and tau oligomers have progressed to clinical trials, with many currently in progress. Biochemical studies of antibody-oligomer complexes have helped identify previously unknown toxic epitopes, thus providing knowledge to the AD field as a whole. This minireview focuses on the efforts to develop passive immunotherapy treatments for AD and discusses the knowledge gained from recent failures and clinical trials in progress.

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Addendum: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

Cited by 70 publications

References 1 publication

Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

Dysregulation of Neuronal Iron Homeostasis as an Alternative Unifying Effect of Mutations Causing Familial Alzheimer’s Disease

MicroRNA-98 reduces amyloid β-protein production and improves oxidative stress and mitochondrial dysfunction through the Notch signaling pathway via HEY2 in Alzheimer's disease mice

Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer’s Disease

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