Alzheimer brain-derived amyloid β-protein impairs synaptic remodeling and memory consolidation

Borlikova, Gilyana; Trejo, Margarita; Mably, Alexandra J.; Donald, Jessica M. Mc; Frigerio, Carlo Sala; Regan, Ciaran M.; Murphy, Keith J.; Masliah, Eliezer; Walsh, Dominic M.

doi:10.1016/j.neurobiolaging.2012.10.028

Cited by 56 publications

(48 citation statements)

References 90 publications

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“…In the eight AD samples, AW7 captured ~90% of all ELISA detectable Aβ (86.8% ± 26.9% of Asp1 Aβ, and 95.6% ± 2.7% of Aβ42). As in our previous work (Shankar et al, 2008, Mc Donald et al, 2010, Borlikova et al, 2013) IP/WB analysis of AD samples revealed two broad bands. By comparison to SeeBlue Plus prestained markers (MWs of 4 kDa, 7 kDa, 16 kDa, 34 kDa, 45 kDa, and 55 kDa), we estimated the apparent molecular weight of each band.…”

Section: Resultssupporting

confidence: 81%

The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species

Donald

O’Malley

et al. 2015

Alzheimer's & Dementia

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Much of our knowledge about Aβ aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less attention has been paid to soluble proteins present in human brain. Here we report that aqueous extracts of AD brain can contain at least four different Aβ assembly forms which include: (i) monomers, (ii) a ~7kDa Aβ species, and larger species which ranged (iii) from ~30–150 kDa, and (iv) from ~160–700 kDa. The ~30–150 kDa species are by far the most prevalent and appear to be built from ~7 kDa Aβ species. The component ~7 kDa Aβ species resist denaturation by chaotropic agents and have a higher Aβ42/Aβ40 ratio than monomers, and are unreactive with antibodies to Asp1 of Aβ or APP residues N-terminal of Asp1. These results recommend further analysis of these brain-derived ~7 kDa Aβ species, the mechanism by which they assemble and the structures which they form.

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Section: Resultssupporting

confidence: 81%

The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species

Donald

O’Malley

et al. 2015

Alzheimer's & Dementia

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“…Grids were analyzed for mitochondrial morphology [49] with a Zeiss OM 10 electron microscope as previously described [40]. Electron micrographs were obtained at a magnification of 25,000X.…”

Section: Methodsmentioning

confidence: 99%

Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure

et al. 2014

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BackgroundAlzheimer’s Disease (AD) and Fronto temporal lobar dementia (FTLD) are common causes of dementia in the aging population for which limited therapeutical options are available. These disorders are associated with Tau accumulation. We have previously shown that CerebrolysinTM (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the behavioral deficits and neuropathological alterations in amyloid precursor protein (APP) transgenic (tg) mouse model of AD by reducing hyper-phosphorylated Tau. CBL has been tested in clinical trials for AD, however it’s potential beneficial effects in FTLD are unknown. For this purpose we sought to investigate the effects of CBL in a tg model of tauopathy. Accordingly, double tg mice expressing mutant Tau under the mThy-1 promoter and GSK3β (to enhance Tau phosphorylation) were treated with CBL and evaluated neuropathologically.ResultsCompared to single Tau tg mice the Tau/GSK3β double tg model displayed elevated levels of Tau phosphorylation and neurodegeneration in the hippocampus. CBL treatment reduced the levels of Tau phosphorylation in the dentate gyrus and the degeneration of pyramidal neurons in the temporal cortex and hippocampus of the Tau/GSK3β double tg mice. Interestingly, the Tau/GSK3β double tg mice also displayed elevated levels of Dynamin-related protein-1 (Drp-1), a protein that hydrolyzes GTP and is required for mitochondrial division. Ultrastructural analysis of the mitochondria in the Tau/GSK3β double tg mice demonstrated increased numbers and fragmentation of mitochondria in comparison to non-tg mice. CBL treatment normalized levels of Drp-1 and restored mitochondrial structure.ConclusionsThese results suggest that the ability of CBL to ameliorate neurodegenerative pathology in the tauopathy model may involve reducing accumulation of hyper-phosphorylated Tau and reducing alterations in mitochondrial biogenesis associated with Tau.

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“…R. Soc. B 369: 20130147 molecular layer of the dentate gyrus when measured 2 days later, after performing a passive avoidance learning task [55]. The persistence of the disruptive effect of Ab 7 days after a single injection may be caused by residual Ab assemblies that are poorly cleared from the brain.…”

Section: Persistence Of the Synaptic Plasticity Disrupting Actions Ofmentioning

confidence: 99%

“…(d) AD brain extracts AD brain extracts were prepared as described previously [55]. Human brain tissue was kindly provided by Matthew P. Frosch, Massachusetts General Hospital and used in accordance with local Ethics Committee guidelines.…”

Section: (C) Chemicalsmentioning

confidence: 99%

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

Klyubin

Ondrejčák²,

Hayes³

et al. 2014

Phil. Trans. R. Soc. B

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Many endogenous factors influence the time course and extent of the detrimental effects of amyloid β-protein (Aβ) on synaptic function. Here, we assessed the impact of varying endogenous glutamatergic and cholinergic transmission by pharmacological means on the disruption of plasticity at hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors (NMDARs) are considered critical in mediating Aβ-induced inhibition of long-term potentiation (LTP). However, intracerebroventricular injection of Aβ 1–42 inhibited not only NMDAR-dependent LTP but also voltage-activated Ca 2+ -dependent LTP induced by strong conditioning stimulation during NMDAR blockade. On the other hand, another form of NMDAR-independent synaptic plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent long-term enhancement, was not hindered by Aβ 1–42 . Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the injection of Aβ 1–42 prevented the inhibition of NMDAR-dependent LTP, whereas the same intervention when introduced after the infusion of Aβ was ineffective. We also examined the duration of action of Aβ, including water soluble Aβ from Alzheimer's disease (AD) brain. Remarkably, the inhibition of LTP induction caused by a single injection of sodium dodecyl sulfate-stable Aβ dimer-containing AD brain extract persisted for at least a week. These findings highlight the need to increase our understanding of non-NMDAR mechanisms and of developing novel means of overcoming, rather than just preventing, the deleterious synaptic actions of Aβ.

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Alzheimer brain-derived amyloid β-protein impairs synaptic remodeling and memory consolidation

Cited by 56 publications

References 90 publications

The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species

The aqueous phase of Alzheimer's disease brain contains assemblies built from ∼4 and ∼7 kDa Aβ species

Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

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