Increased amyloid- levels in APPSWE transgenic mice treated chronically with a physiological high-fat high-cholesterol diet.

Although plasma cholesterol levels are not generally associated with Alzheimer disease (AD) incidence, in vitro studies have found that increased cellular cholesterol levels are associated with increases in -amyloid (A ) production, with a concomitant decrease in sAPPa, the secreted non amyloidogenic fragment of the amyloid precursor protein (APP). In two previous studies using a mouse model for AD-like pathology, non-physiological high-cholesterol diet has been shown to increase plasma and cerebral cholesterol levels, but have resulted in conflicting results on cerebral A levels. In the present study APPSWE male transgenic mice were fed either a chow diet or a physiological high-fat high-cholesterol Western-type diet until the mice reached 1 year of age. Mice fed the Western type diet, compared to the low-fat chow diet, had increased body weight, plasma and cerebral cholesterol levels, as well as a 50% increase in cerebral A levels. Cerebral levels of total APP were not altered while cerebral apoE levels were increased in the mice fed the Western-type diet, versus the chow-fed mice. These data demonstrate that chronic intake of a non-toxic high-cholesterol diet, which is similar to a human diet in fat and cholesterol content, was effective in increasing A levels and further suggests that dietary cholesterol and/or fat may be a risk factor for AD.

Brain region-specific up-regulation of mouse apolipoprotein E by pharmacological estrogen treatments.

Cerebral apolipoprotein E (apoE) has been implicated in neuronal protection and repair. Due to the variable levels and types of estrogen receptors within different brain regions, the effect of estrogen on apoE and the mechanism of this effect may vary within different regions. Ovariectomized female C57BL/6 mice were treated with pharmacological levels of 17 beta-estradiol or placebo for 5 days, resulting in supraphysiological plasma levels of estradiol in the treated mice. ApoE and glial fibrillary acidic protein (GFAP) levels were measured in the cortex, hippocampus and diencephalon. 17 beta-Estradiol up-regulated apoE but not GFAP in the cortex and diencephalon, whereas in the hippocampus, GFAP and apoE were equally up-regulated. Treatment of estrogen receptor (ER) alpha knockout mice with 17 beta-estradiol or treatment of C57BL/6 mice with 17 alpha-estradiol, a poor estrogen receptor agonist, specifically induced apoE in the cortex, but not in the diencephalon. These results indicate that 17 beta-estradiol effects on apoE are either directly or indirectly mediated by ER alpha in the diencephalon, while the effects in the cortex may be mediated by a non-classical mechanism or by ER beta. Measurement of mRNA levels in estrogen versus placebo-treated wild-type mice indicated that the effect of 17 beta-estradiol on apoE was not associated with changes in apoE mRNA levels.