Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease

Pivtoraiko, Violetta N.; Abrahamson, Eric E.; Leurgans, Sue E.; DeKosky, Steven T.; Mufson, Elliott J.; Ikonomović, Miloš D.

doi:10.1016/j.neurobiolaging.2014.06.021

Cited by 27 publications

(23 citation statements)

References 58 publications

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“…Moreover, 5-OP should be of interest to neurochemists as a result of recent findings relating to Alzheimer disease (AD). A portion of Aβ peptide—a contributor to amyloid formation in the brain and a probable neurotoxin contributing to AD pathology—has recently been found to be truncated and to contain an N terminal 5-OP [ 32 , 33 ]. The full-length Aβ and the truncated forms have been designated fl-Aβ and pGlu-Aβ(3-40/42), respectively [ 32 ].…”

Section: Glutamate Formation In the Brain—important Roles Of Glutamentioning

confidence: 99%

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

2016

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Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels.

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Section: Glutamate Formation In the Brain—important Roles Of Glutamentioning

confidence: 99%

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

2016

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“…Also, it has been demonstrated that pGlu-3 Aβ may act as a nidus for template-induced protein misfolding and oligomerization, both with itself and with free Aβ1-42 to generate cytotoxic low-molecular weight oligomers (Nussbaum et al, 2012). Recently, QC expression and pGlu-3 Aβ accumulation in human AD brain has been shown to correlate with cognitive decline (Morawski et al, 2014, Pivtoraiko et al, 2014) and tau pathology (Mandler et al, 2014). Thus, cumulating evidence from human post-mortem tissue and mouse models suggest pGlu-modified Aβ as a species causally involved in AD progression and cognitive decline (Rijal Upadhaya et al, 2014, Saido et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice

Frost

Liu

Rahfeld

et al. 2015

Neurobiology of Aging

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Pyroglutamate-3 amyloid-beta (pGlu-3 Aβ) is an N-terminally truncated Aβ isoform likely playing a decisive role in Alzheimer's disease (AD) pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1ΔE9 mice using a novel pGlu-3 Aβ IgG1 monoclonal antibody (mAb), 07/1 (150 and 500μg i.p. weekly), and compare its efficacy with a general Aβ IgG1 mAb, 3A1 (200μg i.p. weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type (Wt) levels in two hippocampal-dependent tests and partially spared compared to PBS-treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast to 3A1, treatment with 07/1 did not increase the concentration of Aβ in plasma, suggesting different modes of Aβ plaque clearance. In conclusion, early selective targeting of pGlu-3 Aβ by immunotherapy may be effective in lowering cerebral Aβ plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically-modified form of Aβ thereby is unlikely to interfere with potential physiologic function(s) of Aβ that have been proposed.

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“…The PCC is one of the key hubs of the default mode networks and represents early densely amyloid-affected regions whether in patients with AD (Li et al, 2008 ) or in cognitively normal subjects with a positive family history of AD (Mosconi et al, 2010 ). In postmortem study, the concentration of amyloid β (A β) in the PCC GM strongly correlated with episodic memory impairment (Pivtoraiko et al, 2015 ). The PCC is known for its role of modulating information that arrives FG through the interregional connection (Vogt et al, 2006 ), and it is implicated in facial expression processing.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Amyloid Burden with Downstream Fusiform Gyrus Atrophy Correlate with Face Matching Task Scores in Early Stage Alzheimer’s Disease

Chang

Huang

Chen

et al. 2016

Front. Aging Neurosci.

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Purpose: Neuronal activity during face matching shows co-activation of the fusiform gyrus (FG) and areas along the ventral visual network. To elucidate the mechanisms related to the facial discrimination deficits in Alzheimer’s disease (AD), the study evaluates the relationships between β-amyloid (Aβ) load and gray matter (GM) atrophy within the ventral visual network.Methods: Comprehensive cognitive assessments and GM volumetry using 3-dimentional T1-weighted images and AV-45 positron emission tomography (PET) were studied in 44 patients with AD. We used AV-45 PET to measure regional Aβ to analyze the correlations between the regional neocortical AV-45 retention and atrophy in patients with AD.Results: FG volume was positively correlated with the para-hippocampus (β = 0.565, P < 0.001), posterior cingulate cortex (PCC; β = 0.402, P < 0.001), and hippocampus volumes (β = 0.209, P = 0.044). After carefully confounded all possible factors simultaneously, the hippocampus standardized uptake value (SUV) ratio was independently associated with FG volume (β = −0.151, P = 0.017). Furthermore, volumes of the hippocampus (r = 0.473, P = 0.003), para-hippocampus (r = 0.515, P = 0.001), and FG (r = 0.383, P = 0.018) were associated with Benton’s facial recognition test (BFRT).Conclusions: In conclusion, our study indicated that amyloid burden within the hippocampus might contribute to FG cortical hub GM atrophy. While the face matching task scores were related to the FG, hippocampus, and para-hippocampus volumes, concordant changes of the aforementioned three structures suggested the importance of the three ventral visual network hubs in AD.

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Cortical pyroglutamate amyloid-β levels and cognitive decline in Alzheimer's disease

Cited by 27 publications

References 58 publications

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain

An anti-pyroglutamate-3 Aβ vaccine reduces plaques and improves cognition in APPswe/PS1ΔE9 mice

Hippocampal Amyloid Burden with Downstream Fusiform Gyrus Atrophy Correlate with Face Matching Task Scores in Early Stage Alzheimer’s Disease

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