Article

Amyloid-β-induced amyloid-β secretion: a possible feed-forward mechanism in Alzheimer's Disease.

Department of Biochemistry and Molecular Biology and Molecular, Cellular and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO, USA.
Journal of Alzheimer's disease: JAD (impact factor: 3.74). 02/2011; 24(4):681-91. DOI:10.3233/JAD-2011-101899 pp.681-91
Source: PubMed

ABSTRACT Amyloid-β (Aβ) peptides, 36-43 amino acids in length, are produced from β- and γ-secretase cleavage of the amyloid-β protein precursor (AβPP), and are one of the causative agents of Alzheimer's disease (AD). Here we show that an ELISA can detect total rodent Aβ without interference from physiological concentrations of human Aβ. In cultured dissociated rat cortical neurons and rat and mouse hippocampal organotypic slices, we apply the assay to measure the production of Aβ in response to treatment with hydrogen peroxide, a known stimulator of Aβ secretion, or human Aβ dimer/trimer (Aβd/t), fractionated from the culture medium of 7PA2 cells. Peroxide increases Aβ secretion by about 2 fold, similar to results from previous reports that used a different assay. Of greater significance is that physiologically relevant concentrations (~250 pM) of human Aβd/t increase rodent Aβ secretion from cultured rat cortical neurons by >3 fold over 4 days. Surprisingly, neither treatment with peroxide nor human Aβd/t leads to accumulation of intracellular Aβ. Human Aβd/t increased >2 fold the Aβ secreted by organotypic hippocampal slices from tau knock-out mice whether or not they expressed a human tau transgene, suggesting tau plays no role in enhanced Aβ secretion. Together, these results support an Aβ-mediated feed-forward mechanism in AD progression.

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    Article: Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation.
    Richard C Davis, Ian T Marsden, Michael T Maloney, Laurie S Minamide, Marcia Podlisny, Dennis J Selkoe, James R Bamburg
    [show abstract] [hide abstract]
    ABSTRACT: Previously we reported 1 μM synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation) and formation of cofilin-actin rods within rat hippocampal neurons primarily localized to the dentate gyrus. Here we demonstrate that a gel filtration fraction of 7PA2 cell-secreted SDS-stable human Aβ dimers and trimers (Aβd/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Aβ oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Aβ1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50) in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS-stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 Aβd/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state), lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing Aβ monomers are not active, suggesting oxidized SDS-stable Aβ1-42 dimers in a low-n state are the most active rod-inducing species. Aβd/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after Aβd/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Aβd/t, whereas overexpression of a cofilin kinase inhibits Aβd/t-induced rod formation. Together these data support a mechanism by which Aβd/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory.
    Molecular Neurodegeneration 01/2011; 6:10. · 4.28 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

4 days
 
AD progression
 
amyloid-β protein precursor
 
Aβ secretion
 
Aβ-mediated feed-forward mechanism
 
culture medium
 
cultured dissociated rat cortical neurons
 
cultured rat cortical neurons
 
different assay
 
human Aβ dimer/trimer
 
human Aβd/t
 
human Aβd/t increase rodent Aβ secretion
 
human tau transgene
 
known stimulator
 
mouse hippocampal organotypic slices
 
organotypic hippocampal slices
 
Peroxide increases Aβ secretion
 
physiologically relevant concentrations
 
tau knock-out mice
 
total rodent Aβ
 

Ian T Marsden