Early Detection of Cerebral Glucose Uptake Changes in the 5XFAD Mouse

Macdonald, Ian R.; DeBay, Drew R.; Reid, G. Andrew; O’Leary, Timothy P.; Jollymore, Courtney; Mawko, George; Burrell, Steve; Martin, Earl; Bowen, Chris V.; Brown, Richard E.; Darvesh, Sultan

doi:10.2174/1567205011666140505111354

Cited by 65 publications

(86 citation statements)

References 37 publications

(51 reference statements)

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“…Many of these mouse models develop Aβ‐plaque pathology and cognitive dysfunction, but much less is known about how well they recapitulate the sensori‐motor deficits seen in AD. The transgenic 5xFAD mouse develops many pathological changes observed in AD including cognitive impairment a rapid development of Aβ‐plaques, astro‐ and micro‐gliosis, cortical cell loss and reduced cerebral glucose uptake . The 5xFAD mouse also shows motor dysfunction after 9 months of age .…”

Section: Introductionmentioning

confidence: 99%

“…The transgenic 5xFAD mouse develops many pathological changes observed in AD including cognitive impairment 19,20 a rapid development of Aβ-plaques, 20 astro-and micro-gliosis, 21 cortical cell loss 22 and reduced cerebral glucose uptake. 23 The 5xFAD mouse also shows motor dysfunction after 9 months of age. 22,24 Therefore, the 5xFAD mouse may be a particularly useful animal model to examine the development of motor dysfunction in AD, and these motor deficits may be useful in the assessment of novel therapeutics.…”

Section: Introductionmentioning

confidence: 99%

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Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

O’Leary

Mantolino

Stover

et al. 2018

Genes Brain and Behavior

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Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf im on motor function, suggesting that Dysf im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

O’Leary

Mantolino

Stover

et al. 2018

Genes Brain and Behavior

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show abstract

“…Many of these mouse models develop Aβ‐plaque pathology and cognitive dysfunction, but much less is known about their development of age‐related sensorimotor deficits as occurs in AD . The majority of AD mouse models take over 6‐months to develop phenotypic symptoms, but the transgenic 5xFAD mouse model exhibits amyloid plaques before 2 months of age and recapitulates many pathological changes observed in AD, including cognitive impairment, neuronal cell loss and reduced cerebral glucose uptake …”

Section: Introductionmentioning

confidence: 99%

“…9 The majority of AD mouse models take over 6-months to develop phenotypic symptoms, but the transgenic 5xFAD mouse model exhibits amyloid plaques before 2 months of age 10 and recapitulates many pathological changes observed in AD, including cognitive impairment, 10,11 neuronal cell loss 12 and reduced cerebral glucose uptake. 13 Behaviourally, the 5xFAD mice have memory impairments, showed by a lack of recognition for novel objects at 6 to 7 months of age 14 and spatial memory deficits. 15,16 They also have motor impairments after 9 months of age, [17][18][19] age-related deafness 20 and social impairments 11 from 12 months of age.…”

Section: Introductionmentioning

confidence: 99%

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration

Grant

Wong

Fertan

et al. 2018

Genes Brain and Behavior

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Active whisking in mice and rats is one of the fastest behaviours known in mammals and is used to guide complex behaviours such as exploration and navigation. During object contact, whisker movements are actively controlled and undergo robust changes in timing, speed and position. This study quantifies whisker movements in 6‐ to 7‐month old male and female 5xFAD mice, and their C57/SJL F1 wild‐type (WT) controls. As well as genotype, we examined sex differences and the effects of retinal degeneration (rd). Mice were filmed using a high‐speed video camera at 500 frames per second (fps), under infrared light while behaving freely in three tasks: object exploration, sequential object exploration and tunnel running. Measures of whisker position, amplitude, speed and asymmetry were extracted and analysed for each task. The 5xFAD mice had significantly altered whisker angular positions, amplitude and asymmetry during object contacts and female 5xFAD mice with rd had lower mean angular positions during object contact. There were no significant effects of genotype on sequential object exploration or on tunnel running but differences due to sex and rd were found in both tasks, with female mice making larger and faster whisker movements overall, and mice with rd making larger and faster whisker movements during object contact. There were sex differences in whisker movements during sequential object exploration and females with rd had higher whisker retraction speeds in tunnel running. These data show that measuring whisker movements can quantify genotype and sex differences and the effects of rd during exploratory behaviour in these mice.

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“…However these discrepancies may also be accounted for by methodological factors [ 30 ] in addition to strain differences. More recently in vivo hypometabolism in amyloidosis models has been described [ 31 – 33 ].…”

Section: Introductionmentioning

confidence: 99%

In vivo molecular neuroimaging of glucose utilization and its association with fibrillar amyloid-β load in aged APPPS1-21 mice

et al. 2015

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IntroductionRadioligand imaging is a powerful in vivo method to assess the molecular basis of Alzheimer’s Disease. We therefore aimed to visualize the pathological deposition of fibrillar amyloid-β and neuronal dysfunction in aged double transgenic mice.MethodsUsing non-invasive positron emission tomography (PET) we assessed brain glucose utilization with [18F]FDG and fibrillar amyloidosis with [11C]PiB and [18F]AV45 in 12 month old APPPS1-21 (n = 10) mice and their age-matched wild-type controls (n = 15). PET scans were analyzed with statistical parametric mapping (SPM) to detect significant differences in tracer uptake between genotypes. After imaging, mice were sacrificed and ex vivo measures of amyloid-β burden with immunohistochemistry as well as glucose utilization with [14C]-2DG autoradiography were obtained as gold standards.ResultsVoxel-wise SPM analysis revealed significantly decreased [18F]FDG uptake in aged APPPS1-21 mice in comparison to WT with the thalamus (96.96 %, maxT = 3.35) and striatum (61.21 %, maxT = 3.29) demonstrating the most widespread reductions at the threshold of p < 0.01. [11C]PiB binding was significantly increased in APPPS1-21 mice, most notably in the hippocampus (87.84 %, maxT = 7.15) and cortex (69.08 %, maxT = 7.95), as detected by SPM voxel-wise analysis at the threshold of p < 0.01. Using the same threshold [18F]AV45 uptake was comparably lower with less significant differences. Compared to their respective ex vivo equivalents [18F]FDG demonstrated significant positive correlation to [14C]2-DG autoradiography (r = 0.67, p <0.0001) while [11C]PiB and [18F]AV45 binding did not correlate to ex vivo immunohistochemistry for amyloid-β (r = 0.25, p = 0.07 and r = 0.17, p = 0.26 respectively). Lastly no correlation was observed between regions of high amyloid burden and those with decreased glucose utilization (r = 0.001, p = 0.99).ConclusionsOur findings support that fibrillar amyloid-β deposition and reduced glucose utilization can be visualized and quantified with in vivo μPET imaging in aged APPPS1-21 mice. Therefore, the combined use of [18F]FDG and amyloid μPET imaging can shed light on the underlying relationship between fibrillar amyloid-β pathology and neuronal dysfunction.

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Early Detection of Cerebral Glucose Uptake Changes in the 5XFAD Mouse

Cited by 65 publications

References 37 publications

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Whisker exploration behaviours in the 5xFAD mouse are affected by sex and retinal degeneration

In vivo molecular neuroimaging of glucose utilization and its association with fibrillar amyloid-β load in aged APPPS1-21 mice

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