Brain Pathology In Mouse Model Research Articles

Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: Implications for studying obesity–brain interactions in mice

Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.

693. Retrovirally Transduced Bone Marrow Has Effect on Brain Pathology in Mouse Model of Mucopolysaccharidosis IIIB

Top of pageAbstract Mucopolysaccharidosis IIIB (Sanfilippo syndrome type B) is a lysosomal storage disorder resulting from mutations in NAGLU, the gene encoding the enzyme alpha-N-acetylglucosaminidase that is required for the lysosomal degradation of heparan sulfate. The disease is characterized by profound mental retardation and eventual neurodegeneration, accompanied by relatively mild somatic manifestations. There is no available therapy. We have used a mouse knockout model of the disease to test gene therapy by genetically modified bone marrow. Bone marrow from Naglu −/− male mice was transduced with human NAGLU cDNA in an MND-MFG vector, and transplanted into 6–8 week-old lethally irradiated female −/− mice. Sham-treated mice received bone marrow transduced with eGFP cDNA in an MND vector. Analysis of alpha-N-acetylglucosaminidase in serum and white cells at 3 and 6 months after transplantation showed wide variability of expression, ranging from marginal to almost 30 times wild type. Biochemical studies showed that a fraction of normal alpha-N-acetylglucosaminidase activity (as little as provided by transplantation of unmodified +/+ bone marrow) could normalize biochemical defects (glycosaminoglycan storage and beta-hexosaminidase elevation) in liver and spleen. By contrast, only the highest level of activity had any effect on kidney and brain. Morphologic studies by light and electron microscopy showed a decreased number of vacuolated neurons and microglia in several areas of the brain, and an increased number of normal-appearing cells. Quantitation of the change in a section of the cortex is presented in the Table. Immunohistochemistry showed a marked reduction in staining for Lamp1 (a marker of storage in microglia) and for subunit c of ATP synthase (a marker of neuronal pathology). These results show that genetically modified cells of hematopoietic origin can reduce the pathologic manifestations in the brain of the mouse model of mucopolysaccharidosis IIIB.