Mouse Models of Alzheimer’s Disease

Esquerda-Canals, Gisela; Montoliu‐Gaya, Laia; Güell-Bosch, Jofre; Villegas, Sandra

doi:10.3233/jad-170045

Cited by 235 publications

(165 citation statements)

References 71 publications

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“…The role of Aβ, both in Alzheimer’s disease and in normal physiology, remains controversial. Most studies investigating the function of Aβ have been performed in the context of Alzheimer’s pathology using transgenic mice that mimic the human disease 56 . It is well established that insoluble aggregates of Aβ contribute to pathological astrocyte- and microglia-mediated neuroinflammation in Alzheimer’s disease 57 .…”

Section: Discussionmentioning

confidence: 99%

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman

Levinson

Wong

et al. 2019

Preprint

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26Brain metastasis is a significant cause of morbidity and mortality in multiple cancer 27 types and represents an unmet clinical need. The mechanisms that mediate metastatic 28 cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the 29 highest rate of brain metastasis among common cancer types, is an ideal model to 30 study how cancer cells adapt to the brain parenchyma. We performed unbiased 31 proteomics analysis of melanoma short-term cultures, a novel model for the study of 32 brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative 33 pathologies are differentially expressed in melanoma cells explanted from brain 34 metastases compared to those derived from extracranial metastases. This raised the 35 exciting hypothesis that molecular pathways implicated in neurodegenerative disorders 36 are critical for metastatic adaptation to the brain. 37 38Here, we show that melanoma cells require amyloid beta (Ab), a polypeptide heavily 39 implicated in Alzheimer's disease, for growth and survival in the brain parenchyma. 40Melanoma cells produce and secrete Ab, which activates surrounding astrocytes to a 41 pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that 42 pharmacological inhibition of Ab decreases brain metastatic burden. 43 44Our results reveal a mechanistic connection between brain metastasis and Alzheimer's 45 disease -two previously unrelated pathologies, establish Ab as a promising therapeutic 46 target for brain metastasis, and demonstrate suppression of neuroinflammation as a 47 critical feature of metastatic adaptation to the brain parenchyma. 48 49 3 Main 50 51Brain metastasis is the most common form of adult intracranial malignancy 1 and results 52 in severe morbidity and mortality. 40-75% of Stage IV melanoma patients develop brain 53 metastasis 2,3 , reflecting melanoma's striking ability to colonize the brain. Brain 54 metastases are less responsive than extracranial metastases to current cancer 55 therapies 4-6 , and the majority of patients succumb to disease in less than one year 7 . 56 Furthermore, patients with brain metastasis are often excluded from clinical trials and 57 urgently need new clinical options. In recent years, research has started to elucidate the 58 molecular mechanisms contributing to the multi-step process of brain metastasis. Most 59 findings have focused on cancer extravasation across the blood-brain barrier (BBB), 60 which cannot be leveraged therapeutically given that the vast majority of brain 61 metastasis patients will present with extravasated cancer cells at the time of cancer 62 diagnosis. The main bottleneck in the brain metastatic process has been shown to be 63 the successful expansion of a single cell in the brain parenchyma to form a macro-64 metastasis 8 . Recent studies have begun to demonstrate the role of the brain 65 microenvironment in this process. In particular, reactive astrocytes have been shown to 66 interact with cancer cells in the brain 9,10 and exhibit both pro-and anti-...

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Section: Discussionmentioning

confidence: 99%

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Kleffman

Levinson

Wong

et al. 2019

Preprint

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“…The most widely used transgenic models express mutant forms of the amyloid precursor protein (APP) gene, with or without presenilin-1/2 (PSEN1/2), which are associated with autosomal dominant, early-onset AD; or alternatively, MAPT mutations, which cause familial frontotemporal dementia (FTD). These models recapitulate features of AD neuropathology, including plaques or tangles, along with variable degree of neuronal dysfunction/loss, and progressive neurobehavioral impairments (Ballatore et al, 2007;Esquerda-Canals et al, 2017). More recently, gene expression profiling, including RNA-seq, has been applied to elucidate brain transcriptome signatures.…”

Section: Introductionmentioning

confidence: 99%

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

Wan

Al‐Ouran

et al. 2019

Preprint

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Human brain transcriptomes can highlight biological pathways associated with Alzheimer's disease (AD); however, challenges remain to link expression changes with causal triggers. We have examined 30 ADassociated, gene coexpression modules from human brains for overlap with 251 differentially-expressed gene sets from mouse brain RNA-sequencing experiments, including from models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus neurofibrillary tangle pathology and further reveal age-and sex-dependent expression signatures for AD progression. Human coexpression modules enriched for neuronal and/or microglial genes overlap broadly with signatures from mouse models of AD, Huntington's disease, Amyotrophic Lateral Sclerosis, and also aging. Several human AD coexpression modules, including those implicated in the unfolded protein response and oxidative phosphorylation, were not activated in AD models, but instead were detected following other, unexpected mouse genetic manipulations. Our results comprise a powerful, cross-species resource and pinpoint experimental models for diverse features of AD pathophysiology from human brain transcriptomes.

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“…Using a wider variety of model species is therefore advisable, as it may yield results of more general validity. The laboratory rat has been advocated as a well-established experimental animal whose genetic and physiological features are closer to human, and exhibits a richer behavioral repertoire (Do Carmo and Cuello, 2013; Esquerda-Canals et al, 2017). However, the development of transgenic rat models has proven to be considerably more challenging, which has delayed their wider use.…”

Section: Introductionmentioning

confidence: 99%

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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Mouse Models of Alzheimer’s Disease

Cited by 235 publications

References 71 publications

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Functional dissection of Alzheimer’s disease brain gene expression signatures in humans and mouse models

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

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