Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

Abstract

Murine models that mimic the neuropathology of Alzheimer's disease (AD) have the potential to provide insight into the pathogenesis of the disease and lead to new strategies for the therapeutic management of afflicted patients. We used magnetic resonance imaging (MRI), design-based stereology, and high performance liquid chromatography (HPLC) to assess the age-related neuropathology in double transgenic mice that overexpress two AD-related proteins-amyloid precursor protein (APP) and presenilin 1 (PS1)-and age-and gender-matched wild-type (WT) controls. In mice ranging in age from 4-28 months, total volumes of the hippocampal formation (V HF ) and whole brain (V brain ) were quantified by the Cavalieri-point counting method on a systematic-random sample of coronal T2-weighted MRI images; the same stereological methods were used to quantify V HF and V brain after perfusion and histological processing. To assess changes in ADtype beta-amyloid (Aβ) plaques, sections from the hippocampal formation and amylgdaloid complex of mice aged 5, 12, and 15 months were stained by Congo Red histochemistry. In aged mice with large numbers of amyloid plaques, systematic-random samples of sections were stained by GFAP immunocytochemistry to assess gender and genotype effects on total numbers of astrocytes. In addition, levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-HT metabolites were assayed by HPLC in fresh-frozen samples from neocortex, striatum, hippocampus, and brainstem. We confirmed age-related increases in amyloid plaques, beginning with a few plaques at 5 months of age and increasing densities by AGE (2007) 12 and 15 months. At 15 months of age, there were robust genotype effects, but no gender effects, on GFAP-immunopositive astrocytes in the amygdaloid complex and hippocampus. There were no effects on monoamine levels in all brain regions examined, and no volume changes in hippocampal formation or whole brain as quantified on either neuroimages or tissue sections. Strong correlations were present between volume estimates from MRI images and histological sections, with about 85% reduction in mean V HF or mean V brain between MRI and processed histological sections. In summary, these findings show that the double transgenic expression of AD-type mutations is associated with age-related increases in amyloid plaques and astrocytosis; however, this model does not recapitulate the cortical atrophy or neurochemical changes that are characteristic of AD.29:87-96 DOI 10.1007/s11357-007-9035-

Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice

“…Measurements and analyses were performed by an investigator blind to the groups’ identities using the Cavalieri and the Optical Disector/Fractionator and Nucleator methods (Stereo-Investigator; MBF Bioscience, Williston, VT) as previously described (Manaye et al, 2007; Subbiah et al, 1996; West, 1993). The detailed protocols are described in the Supplemental Materials.…”

Early Post-Natal Iron Administration Induces Astroglial Response in the Brain of Adult and Aged Rats

“…Increased astroglial responses precede the oxidative impairments of critical cellular components in an AD animal model (Zhu et al 2008). Recent studies have shown that the number of astrocytes is significantly increased in the hippocampus in APP/PS1 mice compared with age-and gender-matched wild-type littermates (Manaye et al 2007). We have previously described that astrocytic gliosis is an early event in the course of APP/PS1-related pathology and that iron administration during the neonatal period and its late effects are independent of the genetic substrate of the individuals, as similar astrocytic responses were observed Fig.…”

17α-Estradiol Attenuates Neuron Loss in Ovariectomized Dtg AβPP/PS1 Mice

“…Because previous studies have reported increased amyloid load in male dtg AβPP swe /PS1 ΔE9 mice, studies of amyloid load in the present study were limited to the molecular layer in hippocampus of female dtg AβPP swe /PS1 ΔE9 mice. The mean total numbers of pyramidal neurons in CA1 and CA2/3 regions of hippocampus were quantified using the optical fractionator method [49, 50], as previously reported [7, 21, 43, 44, 47, 51–54]. Briefly, the reference spaces on each sampled section were outlined under low power magnification (4X), and volume of Aβ and total number of cells quantified using a high resolution, oil immersion objective (60X, 1.4 numerical aperture).…”

“…Sampling of all parameters was continued to a mean coefficient of error (CE) of 0.05 to 0.10, according to Gundersen et al [55]. All stereological parameters were quantified with assistance from a computerized stereology system by an operator blind to treatment and according to established principles, as detailed previously [21, 43, 47, 48, 51]. …”