APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy

Breyhan, Henning; Wirths, Oliver; Duan, Kailai; Marcello, Andrea; Rettig, Jens; Bayer, Thomas A.

doi:10.1007/s00401-009-0539-7

Cited by 78 publications

(74 citation statements)

References 48 publications

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“…Learning deficits (Billings et al 2005;Giménez-Llort et al 2007;Oakley et al 2006) and reduced brain volume (Breyhan et al 2009) were evident in transgenic APP/PS1 models. However, it seems to be harder to test an exogenous factor that further increases cognitive dysfunction in a model with already severe memory deficits compared with wild-type mice.…”

Section: Discussionmentioning

confidence: 98%

Exposure to Pyrithiamine Increases β-Amyloid Accumulation, Tau Hyperphosphorylation, and Glycogen Synthase Kinase-3 Activity in the Brain

Zhao

Sun

et al. 2010

Neurotox Res

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Decreased thiamine-dependent enzyme activity and/or thiamine deficiency (TD) have been linked to Alzheimer's disease (AD). In this study, we administered pyrithiamine, an anti-thiamine compound, to both APP/PS1 transgenic mice and wild-type littermate control mice; alternatively, we induced TD by thiamine-depleted diet. Pyrithiamine treatment and diet-induced TD impaired the memory of wild-type mice, but had little effect on APP/PS1 mice. Pathophysiologically, pyrithiamine treatment and diet-induced TD aggravated β-amyloid accumulation in the brain. This was demonstrated by increased β-amyloid in the brains of wild-type mice using ELISA and by the number of amyloid plaques in the brains of APP/PS1 transgenic mice using immunochemical staining. Also, enhanced numbers of phosphorylated Tau-positive cells were observed in both APP/PS1 transgenic and wild-type mice. Furthermore, pyrithiamine decreased the phosphorylation rates of glycogen synthase kinase (GSK)-3β and raised its enzymatic activity, but had little influence on GSK-3α. Diet-induced TD reduced the phosphorylated rates and increased the activities of GSK-3, GSK-3α, and GSK-3β. These results suggest that when sufficient thiamine supplement is administered, pyrithiamine can cause AD-like pathological alterations similar to that of diet-induced TD.

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Section: Discussionmentioning

confidence: 98%

Exposure to Pyrithiamine Increases β-Amyloid Accumulation, Tau Hyperphosphorylation, and Glycogen Synthase Kinase-3 Activity in the Brain

Zhao

Sun

et al. 2010

Neurotox Res

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“…In addition, significant neuron loss in the CA1 layer of the hippocampus at 6 months coincides with synaptic deficits, hippocampus atrophy, and a massive increase in intraneuronal and extracellular aggregation of A␤ pE3 . However, neuron loss seen in the CA1 region correlates with intraneuronal rather than extracellular A␤ (59).…”

Section: Pyroglutamate A␤ In Transgenic Alzheimer Mouse Modelsmentioning

confidence: 99%

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Jawhar

Wirths

Bayer

2011

Journal of Biological Chemistry

Self Cite

199

225

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Pyroglutamate-modified amyloid-␤ (A␤ pE3 ) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of A␤ pE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of A␤ pE3 . In this minireview, we summarize the current knowledge on A␤ pE3 , discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.When Alois Alzheimer presented the case of his patient Auguste Deter at the Tübingen meeting of the Southwest German Psychiatrists in 1906, he did not attract much attention or stimulate any discussion in the audience. The young doctor likely would not have believed that, 100 years later, the disease that now holds his name would be the most common cause of dementia and a source of a critical medical and economical problem. At this meeting, Alzheimer presented Auguste Deter's symptoms and reported the histopathological features that are now associated with Alzheimer disease (AD) 2 : neuron loss, extracellular amyloid plaques, and intracellular neurofibrillary tangles. For more than 2 decades, the amyloid hypothesis has been the cardinal hypothesis in describing the sequence of AD etiology. The amyloid hypothesis considers amyloid-␤ (A␤) deposition to be the causative event of AD pathology and that neurofibrillary tangles, cell loss, vascular damage, and dementia occur as a consequence of it (1). However, it has been recently suggested that the extracellular formation of A␤ plaques and other AD pathological events are preceded by intraneuronal A␤ accumulation, giving rise to a modified amyloid hypothesis (2).The story of successful discoveries in modern AD research using novel molecular biological tools started with the biochemical analysis of ␤-amyloid-containing blood vessels (congophilic amyloid angiopathy) (3) and amyloid plaques consisting of A␤ (4), which led to the isolation and sequencing of the gene encoding the larger amyloid precursor protein (APP) (5, 6).In vitro and in vivo analyses of amyloid deposits in AD revealed various N-and C-terminal variants (4, 7, 8). Increased C-terminal length of A␤ (from A␤ x-40 to A␤ x-42 ) in AD enhanced aggregation and early deposition and promoted the toxicity of A␤ (9 -11). Recently, A␤ 1-43 has been discussed as a novel toxic peptide in AD (12).Beside A␤ peptides, starting with aspartate as the first amino acid (A␤ 1-x ), several N-terminally truncated and modified A␤ species have been described (4, 13-15). Among A␤ species present in AD plaques, Lewis et al. (16) reported that A␤ 4 -42 is a relatively abundant species in AD, aged control, and vascular dementia patients. Using immunoprecipitation in combination with mass spectrome...

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“…Studies of the APP SL PS1KI line showed some evidence of pE3-A␤ neurotoxicity in these mice (Christensen et al, 2008;Breyhan et al, 2009;Wirths et al, 2010), and the development of novel imaging systems has further supported the role of pE3-A␤ as an important component in the amyloid deposits of transgenic mouse models (Maeda et al, 2007). To investigate the role of pE3-A␤ as a potential driver of neurotoxicity, we generated the TBA2.1 and TBA2.2 mouse lines expressing N-terminally truncated A␤ within the secretory pathway, resulting in significant pE3-A␤ formation promoted by enzymatic activity of QC, which colocalizes with prohormone convertases and is sorted to secretory vesicles.…”

Section: Discussionmentioning

confidence: 99%

Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate–Aβ Formation

Alexandru¹,

Jagla²,

Graubner³

et al. 2011

J. Neurosci.

102

138

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Posttranslational amyloid-␤ (A␤) modification is considered to play an important role in Alzheimer's disease (AD)etiology. An N-terminally modified A␤ species, pyroglutamate-amyloid-␤ (pE3-A␤), has been described as a major constituent of A␤ deposits specific to human AD but absent in normal aging. Formed via cyclization of truncated A␤ species by glutaminyl cyclase (QC; QPCT) and/or its isoenzyme (isoQC; QPCTL), pE3-A␤ aggregates rapidly and is known to seed additional A␤ aggregation. To directly investigate pE3-A␤ toxicity in vivo, we generated and characterized transgenic TBA2.1 and TBA2.2 mice, which express truncated mutant human A␤. Along with a rapidly developing behavioral phenotype, these mice showed progressively accumulating A␤ and pE3-A␤ deposits in brain regions of neuronal loss, impaired long-term potentiation, microglial activation, and astrocytosis. Illustrating a threshold for pE3-A␤ neurotoxicity, this phenotype was not found in heterozygous animals but in homozygous TBA2.1 or double-heterozygous TBA2.1/2.2 animals only. A significant amount of pE3-A␤ formation was shown to be QC-dependent, because crossbreeding of TBA2.1 with QC knock-out, but not isoQC knock-out, mice significantly reduced pE3-A␤ levels. Hence, lowering the rate of QC-dependent posttranslational pE3-A␤ formation can, in turn, lower the amount of neurotoxic A␤ species in AD.

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APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy

Cited by 78 publications

References 48 publications

Exposure to Pyrithiamine Increases β-Amyloid Accumulation, Tau Hyperphosphorylation, and Glycogen Synthase Kinase-3 Activity in the Brain

Exposure to Pyrithiamine Increases β-Amyloid Accumulation, Tau Hyperphosphorylation, and Glycogen Synthase Kinase-3 Activity in the Brain

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Selective Hippocampal Neurodegeneration in Transgenic Mice Expressing Small Amounts of Truncated Aβ Is Induced by Pyroglutamate–Aβ Formation

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