1
Affected in AD, as well as other neurodegenerative diseases [47,50, 53,56,59,60,65,68,69,71], and cerebellar degeneration causes cognitive impairment [49,57-59,62,63,66,67,72]. Previous studies demonstrated significant structural, functional, and metabolic abnormalities in AD cerebella [57-59,82], including insulin and IGF resistance [30],similar to the findings in more traditional targets of AD,
1
Or NDEA-associated neurodegeneration and insulin/IGF resistance were likely mediated by increased brain ceramide levels. Those studies demonstrated strikingly increased expression of several genes regulating ceramide production via both de novo biosynthesis or sphingomyelin degradation pathways in NDEA-treated rats, irrespective of chronic HFD feeding. Since NDEA is lipid soluble [115,116] and can
1
Ative stress with lipid peroxidation, as occur in AD. The finding that chronic HFD feeding did not significantly alter tau or AbPP expression also supports our previous conclusion that HFD feeding contributes to, but is not sufficient to cause AD-type neurodegeneration [45,46]. The combined effect of early, limited NDEA exposure plus chronic HFD feeding significantly reduced insulin and ChAT mRNA
1
S, could result in cytoskeletal collapse and synaptic disconnection. Alternatively, the finding could reflect neuronal loss associated with neurodegeneration. The reduced levels of ChAT reflect deficits in acetylcholine homeostasis that contribute to cognitive impairment with neurodegeneration [101,102]. Correspondingly, in preliminary studies, we detected evidence of significant spatial learning
1
Ds, and cholesterol levels compared with LFD+VEH and LFD +NDEA treated groups. In addition, the serum free fatty acid level was significantly lower in the LFD+NDEA compared with LFD+VEH treated rats, whereas the triglyceride and cholesterol levels were similar in the two groups. Therefore, hyperglycemia, hyper-insulinemia, and hyper-leptinemia were features of chronic HFD feeding, and worsened by
1
F vehicle or NDEA (N = 12/group) on alternate days beginning on P3. From P21 (weaning), rats were fed with high fat (60 of calories) or low fat (5 of calories) diets for 8 weeks, after which they were sacrificed to harvest cerebella for histopathological and immunohistochemical staining studies. Cerebella were preserved in Histofix and paraffin-embedded sections (8 microns) were stained with (A1
1
Could serve as biomarkers of insulin-resistance mediated neurodegeneration. Finally, the findings suggest that our insulin resistance disease epidemics are linked to sub-mutagenicTong et al. BMC Endocrine Disorders 2010, 10:4 http://www.biomedcentral.com/1472-6823/10/Page 13 ofexposures to nitrosamines and related compounds, combined with chronic consumption of high fat content foods, indicating t
1
Ation with impairments in insulin/IGF signaling mechanisms, and deficits in cholinergic and neuronal cytoskeletal gene and protein expression in brain, whereas chronic HFD feeding alone produces more restrictive deficits in insulin/IGF signaling mechanisms with reduced ChAT expression and increased oxidative stress. The combined exposures caused overlapping structural and molecular abnormalities t