Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease

Hanzel, Cecilia E.; Pichet-Binette, Alexa; Pimentel, Luisa; Iulita, M. Florencia; Allard, S.T.M.; Ducatenzeiler, Adriana; Carmo, Sonia Do; Cuello, A. Claudio

doi:10.1016/j.neurobiolaging.2014.03.026

Cited by 130 publications

(92 citation statements)

References 65 publications

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“…Interestingly, a recent report showed that Prok2 mRNA is upregulated by Abeta treatment in the rat cortex and hippocampus, and Prok2 antagonist protects the brain from Abeta-mediated neurotoxicity (Severini et al, 2015). The higher levels of Prok2 mRNA in the McGill cortex and hippocampus might also be due to a general increase of proinflammatory markers as was previously reported in the hippocampus of McGill rats (Hanzel et al, 2014). Finally, the higher Prok2 mRNA levels correlate with observed increased activity of McGill rats, because prokineticin 2 plays a role in maintaining the awake state (Hu et al, 2007).…”

Section: Discussionsupporting

confidence: 61%

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity

Petrásek

Vojtěchová

Lobellová

et al. 2018

Front. Aging Neurosci.

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The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4–7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene Bmal1 was found to be increased in the parietal cortex and cerebellum, while Nr1d1 expression was not changed. The clock-controlled gene Prok2 expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.

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Section: Discussionsupporting

confidence: 61%

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity

Petrásek

Vojtěchová

Lobellová

et al. 2018

Front. Aging Neurosci.

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“…On the other hand, amyloid-independent microglia activation, as it for example occurs in patients with multiple sclerosis or HIV, was found to have no relevant impact on the development of Alzheimer-associated cortical pathology [49, 142]. Furthermore, signs of inflammation have been observed in multiple animal models before plaques [79, 213, 219] or tangles [219] were present, which may suggest that inflammation—if it plays a causative role in sporadic Alzheimer diseases—plays a role early during the development of the disease. We, however, failed to observe significant microglia activation in transgenic amyloid mouse models prior to the occurrence of amyloid plaques [91].…”

Section: Intraneuronal Amyloid Betamentioning

confidence: 99%

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

et al. 2015

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Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer’s disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer’s disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer’s disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer’s disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder.

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“…Microglia are converted into a proinflammatory, "activated" phenotype by exposure to extracellular soluble and fibrillar Aβ [12], and through direct interactions with neurons that exhibit accumulation of intraneuronal Aβ [13]. Once recruited to plaques [14,15], microglia undergo morphologic changes, such as increased soma size and thickened processes that they invest into the plaques [15].…”

Section: Microglia In the Alzheimer's Disease Brainmentioning

confidence: 99%

The Evolving Biology of Microglia in Alzheimer's Disease

2015

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Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease

Cited by 130 publications

References 65 publications

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

The Evolving Biology of Microglia in Alzheimer's Disease

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