APP21 transgenic rats develop age-dependent cognitive impairment and microglia accumulation within white matter tracts

Weishaupt, Nina; Liu, Qingfan; Shin, Sheojung; Singh, Rajendra; Ağca, Yüksel; Ağca, Cansu; Hachinski, Vladimir; Whitehead, Shawn N.

doi:10.1186/s12974-018-1273-7

Cited by 17 publications

(19 citation statements)

References 26 publications

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“…TSPO immunohistochemistry cell count of the day 28 infarct also correlated better with the UR calculated using the cerebellum (R 2 = 0.63, P = 0.0191) instead of the region contralateral to the infarct (R 2 = 0.47, P = ns) or periaqueductal gray (R 2 = 0.36, P = ns) (Additional file 1: Online Fig. 4) [12,13]. Genotype did not have a significant effect (P = ns, two-way ANOVA, Fig.…”

Section: The Cerebellum Is An Appropriate Pseudoreference Region For mentioning

confidence: 92%

“…Randomization was accomplished using rat ids. Genotype was validated with PCR as previously described [13].…”

Section: Animals and Experimental Designmentioning

confidence: 99%

“…MHCII molecules are correlated to cognitive dysfunction throughout AD and diffusely overexpressed in the WM microglia of patients with early-onset AD [ 1 , 10 ]. Previously, our group correlated diffuse MHCII activated microglia in WM with cognitive dysfunction in a prodromal transgenic rat model of AD that overexpresses human Swedish- and Indiana-mutated amyloid precursor protein (TgAPP21) to produce high levels of beta-amyloid without depositing amyloid plaques [ 11 – 13 ]. We further demonstrated the importance of diffuse MHCII activated microglia by detecting them in WM remote to an ischemic subcortical stroke in an endothelin-1 (ET1) rat model that also exhibits executive dysfunction [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

Al-Khishman

Roseborough

et al. 2020

EJNMMI Res

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Background Accurate and sensitive imaging biomarkers are required to study the progression of white matter (WM) inflammation in neurodegenerative diseases. Radioligands targeting the translocator protein (TSPO) are considered sensitive indicators of neuroinflammation, but it is not clear how well the expression of TSPO coincides with major histocompatibility complex class II (MHCII) molecules in WM. This study aimed to test the ability of TSPO to detect activated WM microglia that are immunohistochemically positive for MHCII in rat models of prodromal Alzheimer’s disease and acute subcortical stroke. Methods Fischer 344 wild-type (n = 12) and TgAPP21 (n = 11) rats were imaged with [18F]FEPPA PET and MRI to investigate TSPO tracer uptake in the corpus callosum, a WM region known to have high levels of MHCII activated microglia in TgAPP21 rats. Wild-type rats subsequently received an endothelin-1 (ET1) subcortical stroke and were imaged at days 7 and 28 post-stroke before immunohistochemistry of TSPO, GFAP, iNOS, and the MHCII rat antigen, OX6. Results [18F]FEPPA PET was not significantly affected by genotype in WM and only detected increases near the ET1 infarct (P = 0.033, infarct/cerebellum uptake ratio: baseline = 0.94 ± 0.16; day 7 = 2.10 ± 0.78; day 28 = 1.77 ± 0.35). Immunohistochemistry confirmed that only the infarct (TSPO cells/mm2: day 7 = 555 ± 181; day 28 = 307 ± 153) and WM that is proximal to the infarct had TSPO expression (TSPO cells/mm2: day 7 = 113 ± 93; day 28 = 5 ± 7). TSPO and iNOS were not able to detect the chronic WM microglial activation that was detected with MHCII in the contralateral corpus callosum (day 28 OX6% area: saline = 0.62 ± 0.38; stroke = 4.30 ± 2.83; P = .029). Conclusion TSPO was only expressed in the stroke-induced insult and proximal tissue and therefore was unable to detect remote and non-insult-related chronically activated microglia overexpressing MHCII in WM. This suggests that research in neuroinflammation, particularly in the WM, would benefit from MHCII-sensitive radiotracers.

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Section: The Cerebellum Is An Appropriate Pseudoreference Region For mentioning

confidence: 92%

“…Randomization was accomplished using rat ids. Genotype was validated with PCR as previously described [13].…”

Section: Animals and Experimental Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

Al-Khishman

Roseborough

et al. 2020

EJNMMI Res

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“…There were no apparent differences among the groups. Microglia activation in the white matter, detected with the OX-6 immunostaining, has been shown to undergo an age-related increase in the TG rats compared to WT rats [31]. The images of the OX-6 activated microglia in three white matter regions from the 3-month-old TG animal demonstrate that there is a low activation of microglia in the young animal ( Fig.…”

Section: Microglia Activationmentioning

confidence: 83%

“…The present study was undertaken to better understand the relation between metabolic abnormalities and prodromal AD dementia, particularly studying the impact on changes in white matter inflammatory pathology and coincident cognitive deficits. The comorbidity of prodromal AD with metabolic syndrome was examined in a novel APP21 transgenic (TG) rat model of pre-AD [30,31] created on a Fischer 344 background which carries a human APP (hAPP) gene with Swedish and Indiana mutations, implicated in early-onset AD. This rat has been previously shown to express high levels of human brain APP and serum β-amyloid (Aβ1-40 and 1-42) without spontaneous Aβ plaques deposition in brain tissue with age [32,33].…”

Section: Introductionmentioning

confidence: 99%

White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer’s disease rat model

Ivanova

Liu

Ağca

et al. 2020

J Neuroinflammation

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Background: Metabolic syndrome, the development of which is associated with high-caloric Western diet (HCD) intake, represent a risk factor for mild cognitive impairment (MCI) and dementia including Alzheimer's disease (AD) later in life. This study aimed to investigate the effect of diet-induced metabolic disturbances on white matter neuroinflammation and cognitive function in a transgenic (TG) Fischer 344 rat carrying a human β-amyloid precursor protein (APP) gene with Swedish and Indiana mutations (APP21 TG), a model of pre-AD and MCI. Methods: TG and wildtype (WT) rats received either a HCD with 40% kJ from fat supplemented with 20% corn syrup drink or a standard diet for 12 weeks. Body weight, caloric intake, and blood pressure were measured repeatedly. End-point changes in glucose and lipid metabolism were also assessed. Open field task was used for assessment of activity; Morris water maze was used to assess spatial learning and memory. Cerebral white matter microglia and astrocytes, hippocampal neurons, and neuronal synapses were examined using immunohistochemistry. Results: Rats maintained on the HCD developed significant obesity, visceral adiposity, dyslipidemia, and hyperinsulinemia, but did not become hypertensive. Impaired glucose tolerance was observed only in WT rats on the HCD. Total microglia number, activated OX-6+ microglia, as well as GFAP+ astrocytes located predominantly in the white matter were greater in the APP21 TG rat model in comparison to WT rats. HCD-driven metabolic perturbations further exacerbated white matter microgliosis and microglia cell activation in the APP21 TG rats and led to detectable changes in spatial reference memory in the comorbid prodromal AD and metabolic syndrome group compared to WT control rats. Neuronal density in the CA1 subregion of the hippocampus was not different between the experimental groups. Synaptic density in the CA1 and CA3 hippocampal subregions was lower in the TG rats compared to WT rats; however, there was no additional effect of the co-morbidity on this measure. Conclusions: These results suggest that white matter neuroinflammation might be one of the possible processes of early interaction of metabolic syndrome with MCI and pre-AD and could be one of the early brain pathologies contributing to cognitive deficits observed in mild cognitive impairment and dementia, including AD cases.

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TSPO imaging in animal models of brain diseases

Camp

Lavisse

Roost

et al. 2021

Eur J Nucl Med Mol Imaging

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Over the last 30 years, the 18-kDa TSPO protein has been considered as the PET imaging biomarker of reference to measure increased neuroinflammation. Generally assumed to image activated microglia, TSPO has also been detected in endothelial cells and activated astrocytes. Here, we provide an exhaustive overview of the recent literature on the TSPO-PET imaging (i) in the search and development of new TSPO tracers and (ii) in the understanding of acute and chronic neuroinflammation in animal models of neurological disorders. Generally, studies testing new TSPO radiotracers against the prototypic [11C]-R-PK11195 or more recent competitors use models of acute focal neuroinflammation (e.g. stroke or lipopolysaccharide injection). These studies have led to the development of over 60 new tracers during the last 15 years. These studies highlighted that interpretation of TSPO-PET is easier in acute models of focal lesions, whereas in chronic models with lower or diffuse microglial activation, such as models of Alzheimer’s disease or Parkinson’s disease, TSPO quantification for detection of neuroinflammation is more challenging, mirroring what is observed in clinic. Moreover, technical limitations of preclinical scanners provide a drawback when studying modest neuroinflammation in small brains (e.g. in mice). Overall, this review underlines the value of TSPO imaging to study the time course or response to treatment of neuroinflammation in acute or chronic models of diseases. As such, TSPO remains the gold standard biomarker reference for neuroinflammation, waiting for new radioligands for other, more specific targets for neuroinflammatory processes and/or immune cells to emerge.

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APP21 transgenic rats develop age-dependent cognitive impairment and microglia accumulation within white matter tracts

Cited by 17 publications

References 26 publications

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

TSPO PET detects acute neuroinflammation but not diffuse chronically activated MHCII microglia in the rat

White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer’s disease rat model

TSPO imaging in animal models of brain diseases

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