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White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer's disease rat model.
J Neuroinflammation. 2020 Jan 21; 17(1):29.JN

Abstract

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.

Authors+Show Affiliations

Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada. nivanov3@uwo.ca.Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA.Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA.School of Kinesiology, Western University, London, ON, Canada.Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, N6A 5C1, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31964387

Citation

Ivanova, Nadezda, et al. "White Matter Inflammation and Cognitive Function in a Co-morbid Metabolic Syndrome and Prodromal Alzheimer's Disease Rat Model." Journal of Neuroinflammation, vol. 17, no. 1, 2020, p. 29.
Ivanova N, Liu Q, Agca C, et al. White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer's disease rat model. J Neuroinflammation. 2020;17(1):29.
Ivanova, N., Liu, Q., Agca, C., Agca, Y., Noble, E. G., Whitehead, S. N., & Cechetto, D. F. (2020). White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer's disease rat model. Journal of Neuroinflammation, 17(1), 29. https://doi.org/10.1186/s12974-020-1698-7
Ivanova N, et al. White Matter Inflammation and Cognitive Function in a Co-morbid Metabolic Syndrome and Prodromal Alzheimer's Disease Rat Model. J Neuroinflammation. 2020 Jan 21;17(1):29. PubMed PMID: 31964387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - White matter inflammation and cognitive function in a co-morbid metabolic syndrome and prodromal Alzheimer's disease rat model. AU - Ivanova,Nadezda, AU - Liu,Qingfan, AU - Agca,Cansu, AU - Agca,Yuksel, AU - Noble,Earl G, AU - Whitehead,Shawn Narain, AU - Cechetto,David Floyd, Y1 - 2020/01/21/ PY - 2019/04/04/received PY - 2020/01/02/accepted PY - 2020/1/23/entrez PY - 2020/1/23/pubmed PY - 2020/11/20/medline KW - APP21 Transgenic rat KW - Hypercaloric diet KW - Metabolic syndrome KW - Microglia KW - Prodromal Alzheimer’s disease KW - White matter inflammation SP - 29 EP - 29 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 17 IS - 1 N2 - 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. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/31964387/White_matter_inflammation_and_cognitive_function_in_a_co_morbid_metabolic_syndrome_and_prodromal_Alzheimer's_disease_rat_model_ DB - PRIME DP - Unbound Medicine ER -