Early-onset dysfunction of retrosplenial cortex precedes overt amyloid plaque formation in Tg2576 mice

Poirier, Guillaume L.; Amin, Eman; Good, Mark Andrew; Aggleton, John Patrick

doi:10.1016/j.neuroscience.2010.11.025

Cited by 28 publications

(24 citation statements)

References 109 publications

(145 reference statements)

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“…Both studies also provided evidence that MB decreased soluble levels of tau or amyloid. These results are of interest because they are in agreement with evidence showing that mitochondrial dysfunction, including changes in cytochrome oxidase expression precede protein aggregation pathology in models of amyloid deposition (Valla et al, 2010; Poirier et al, 2011). …”

Section: Mb As a Memory-improving Drugsupporting

confidence: 86%

Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

Rojas

Bruchey

González-Lima

2012

Progress in Neurobiology

148

181

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This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue’s action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment.

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Section: Mb As a Memory-improving Drugsupporting

confidence: 86%

Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

Rojas

Bruchey

González-Lima

2012

Progress in Neurobiology

148

181

View full text Add to dashboard Cite

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“…However, similar to the situation in the entorhinal cortex, it is the layer that receives strong inputs from the dorsal subiculum that preferentially expresses the plaques (Witter et al ., ). This pattern of plaque deposition in superficial layers of the retrosplenial cortex has also been reported in the 3xTg‐AD (Robertson et al ., ), APP/PS1 (van Groen et al ., ) and Tg2576 (Poirier et al ., ) mouse models. The pattern of plaques also largely overlaps with the distribution of cholinergic axons originating in the medial septum, and based on lesioning of these afferents it has been suggested that Aβ can be released from the septal projections in superficial layers of the retrosplenial cortex (Robertson et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer's disease

Heggland

Storkaas

Soligard

et al. 2015

Eur J of Neuroscience

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The main hallmarks of Alzheimer's disease (AD) are senile plaques, neurofibrillary tangles and neuronal death. The McGill-R-Thy1-APP rat is one of the few transgenic rat models of AD that displays progressive amyloid pathology. This study aimed to further characterise this rat model, focusing on the pathological changes in the hippocampal formation and the parahippocampal region. These structures, that are important for episodic memory and spatial navigation, are affected in the early stages of the disease. This study used unbiased stereology to investigate possible neuronal loss in the CA1, subiculum and entorhinal cortex of 18-month-old homozygous McGill-R-Thy1-APP rats, and also quantified the plaque load in all the areas of the hippocampal formation and parahippocampal region from 9 to 18 months old. A significant reduction of neurons at 18 months was only seen in the subiculum. The first plaque pathology was seen at 9 months in the subiculum. Although the quantified plaque load was variable between animals, the pattern of spatiotemporal progression was similar for all animals. The spread of plaque pathology mainly affected anatomically connected regions. Overall, the plaque pathology observed in the transgenic rats was similar to the early phases of amyloid beta (Aβ)-deposition described in human patients. The findings here thus indicate that the McGill-R-Thy1-APP rat could be a good model of the Aβ pathology in AD, but less so with respect to neuron loss.

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“…This report showed increased complex IV activity only in specific regions of the brain. In another report, complex IV activity increased in Tg2576 mice at 5 months of age compared to controls [ 77 ]. Another group found similar results with these mice at 7 months of age [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPPswe/PS1 mice

O'Neal-Moffitt

Delic

Bradshaw

et al. 2015

Mol Neurodegeneration

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BackgroundAlzheimer’s disease (AD) underlies dementia for millions of people worldwide, and its occurrence is set to double in the next 20 years. Currently, approved drugs for treating AD only marginally ameliorate cognitive deficits, and provide limited symptomatic relief, while newer substances under therapeutic development are potentially years away from benefiting patients. Melatonin (MEL) for insomnia has been proven safe with >15 years of over-the-counter access in the US. MEL exerts multiple complementary mechanisms of action against AD in animal models; thus it may be an excellent disease-modifying therapeutic. While presumed to provide neuroprotection via activation of known G-protein-coupled melatonin receptors (MTNRs), some data indicate MEL acts intracellularly to protect mitochondria and neurons by scavenging reactive oxygen species and reducing free radical formation. We examined whether genetic deletion of MTNRs abolishes MEL’s neuroprotective actions in the AβPPswe/PSEN1dE9 mouse model of AD (2xAD). Beginning at 4 months of age, both AD and control mice either with or without both MTNRs were administered either MEL or vehicle in drinking water for 12 months.ResultsBehavioral and cognitive assessments of 15-month-old AD mice revealed receptor-dependent effects of MEL on spatial learning and memory (Barnes maze, Morris Water Maze), but receptor-independent neuroprotective actions of MEL on non-spatial cognitive performance (Novel Object Recognition Test). Similarly, amyloid plaque loads in hippocampus and frontal cortex, as well as plasma Aβ1–42 levels, were significantly reduced by MEL in a receptor-independent manner, in contrast to MEL’s efficacy in reducing cortical antioxidant gene expression (Catalase, SOD1, Glutathione Peroxidase-1, Nrf2) only when receptors were present. Increased cytochrome c oxidase activity was seen in 16mo AD mice as compared to non-AD control mice. This increase was completely prevented by MEL treatment of 2xAD/MTNR+ mice, but only partially prevented in 2xAD/MTNR- mice, consistent with mixed receptor-dependent and independent effects of MEL on this measure of mitochondrial function.ConclusionsThese findings demonstrate that prophylactic MEL significantly reduces AD neuropathology and associated cognitive deficits in a manner that is independent of antioxidant pathways. Future identification of direct molecular targets for MEL action in the brain should open new vistas for development of better AD therapeutics.

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Early-onset dysfunction of retrosplenial cortex precedes overt amyloid plaque formation in Tg2576 mice

Cited by 28 publications

References 109 publications

Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

Stereological estimation of neuron number and plaque load in the hippocampal region of a transgenic rat model of Alzheimer's disease

Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPPswe/PS1 mice

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