Physicochemical characteristics of soluble oligomeric Aβ and their pathologic role in Alzheimer's disease

  title={Physicochemical characteristics of soluble oligomeric A$\beta$ and their pathologic role in Alzheimer's disease},
  author={Desiree Watson and Eduardo Miguel Casta{\~n}o and Tyler A. Kokjohn and Yu-Min Kuo and Yuri L. Lyubchenko and David J Pinsky and E. Sander Connolly and Chera L. Esh and Dean C. Luehrs and William B. Stine and L. Rowse and Mark R. Emmerling and Alex E. Roher},
  journal={Neurological Research},
  pages={869 - 881}
Abstract Extracellular fibrillar amyloid deposits are prominent and universal Alzheimer's disease (AD) features, but senile plaque abundance does not always correlate directly with the degree of dementia exhibited by AD patients. The mechanism(s) and dynamics of Aβ fibril genesis and deposition remain obscure. Enhanced Aβ synthesis rates coupled with decreased degradative enzyme production and accumulating physical modifications that dampen proteolysis may all enhance amyloid deposit formation… 
A b structural diversity and Alzheimer ' s disease pathogenesis
It is proposed that amplified production of some APP/Ab 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.
Molecular subtypes of Alzheimer’s disease
Overall these data suggest that the assembly of mixtures of Aβ peptides into different Aβ seeds leads to the formation of distinct subtypes of amyloid having distinctive physicochemical and biological properties which result in the generation of distinct AD molecular subgroups.
APP/Aβ structural diversity and Alzheimer's disease pathogenesis
Characterisation of different amyloid-ß aggregates in Alzheimer's disease
Experimental evidence is provided that different soluble A�-aggregates are highly potent synaptotoxins, impairing neurotransmission by different mechanisms, revealing that virtually similar aggregates can have opponent pathogenic effects; thus, morphology only does not explain observed pathogenicity.
Deficits in the miRNA-34a-regulated endogenous TREM2 phagocytosis sensor-receptor in Alzheimer's disease (AD); an update
This short paper is an update on some very recent observations on TREM2 neurobiology, on newly discovered roles for miRNA-34a-mediated signaling in human degenerative disease, including mi RNA-34A-mediated effects on T REM2 expression, and how dysfunctional TREM1 signaling may contribute to amyloidogenesis in AD and in related progressive, inflammatory neurodegenerative diseases of the human CNS.
Diffusible, highly bioactive oligomers represent a critical minority of soluble Aβ in Alzheimer’s disease brain
Surprisingly, the bulk of Aβ extractable from AD brain was innocuous, and only the small portion that was aqueously diffusible caused toxicity, predicting that generic anti-oligomer therapies, including Aβ antibodies now in trials, may be bound up by the large pool of inactive oligomers, whereas agents that specifically target the small pool of diffusable, bioactive Aβ would be more useful.
Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis.
Tissue histology and biochemically characterized the remnant amyloid peptides in the gray and white matter and leptomeningeal/cortical vessels of two AN-1792-vaccinated patients and suggest that although immunization disruptedAmyloid deposits, vascular capture prevented large-scale egress of Abeta peptides.
Role of Calcium in Inflammation: Relevance to Alzheimer's Disease
The data suggest that either activity or expression of Cox-2 is increased in TgAPPsw mice brains as a function of age, contributing to an increased production of pro-inflammatory eicosanoids and TNFα.
Modeling Amyloid-Beta as Homogeneous Dodecamers and in Complex with Cellular Prion Protein
Molecular dynamics simulations for dodecameric assemblies of Aβ comprised of monomers having a single, short antiparallel β-hairpin at the C-terminus are performed and are found to be quite stable within the hydrophobic core, indicating that highly ordered assemblies are not required for stability and less ordered oligomers are a viable component in the population of soluble oligomers.


Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease
  • C. Glabe
  • Biology
    Journal of Molecular Neuroscience
  • 2007
The novel view that amyloid deposits and some of the early events of amyloids pathogenesis initiate randomly within single cells in Alzheimer’s disease is provided.
Protofibrillar Intermediates of Amyloid β-Protein Induce Acute Electrophysiological Changes and Progressive Neurotoxicity in Cortical Neurons
The results raise the possibility that the preclinical and early clinical progression of AD is driven in part by the accumulation of specific Aβ assembly intermediates formed during the process of fibrillogenesis, and suggest that PF have inherent biological activity similar to that of mature fibrils.
Presence of soluble amyloid β–peptide precedes amyloid plaque formation in Down's syndrome
It is reported that soluble Aβ42 is present in the brains of DS–affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age–matched controls.
Soluble Amyloid b Peptide Concentration as a Predictor of Synaptic Change in Alzheimer’s Disease
Investigation revealed that A b 40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with A b 42, and concentrations of soluble A b clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss.
Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease
The genetic evidence strongly supports the view that Aβ amyloid production is central to the cause of Alzheimer's disease, and the concept of several interacting pools of Aβ, that is, a large relatively static insoluble pool that is derived from a constantly turning over smaller soluble pool, is supported.
Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia
The results support the idea that the non‐fibrillar soluble aggregates are the pathogenic species, which may play a central role in the pathogenesis of FDD, and imply that similar mechanism may also be involved in other neurodegenerative diseases associated with amyloid deposits.
The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain.
It is concluded that the pathogenically critical process of Abeta oligomers, principally dimers, in primary human neurons and in neuronal and nonneural cell lines begins intraneuronally.
Structural studies of soluble oligomers of the alzheimer β-amyloid peptide
The findings indicate that soluble oligomeric forms of Aβ peptides can be trapped for extended periods of time, enabling their study by high resolution techniques that would not otherwise be possible.
Heterogeneous amyloid-formed ion channels as a common cytotoxic mechanism
It is concluded that conformation-based channel diversity is an important mechanism for enhancing the toxicity of amyloid-forming peptides and multiple therapeutic interventions may be necessary for blocking and reversing heterogeneous channel formations and preventing their associated diseases.