Alteration of Aß metabolism-related molecules in predementia induced by AlCl3 and D-galactose.

The purpose of this study was to look for alterations in ß-amyloid peptide (Aß) metabolism-related molecules in predementia, the early stage of Alzheimer's disease (AD). AlCl3 (Al) and d-galactose (D-gal) were used to induce the mouse model for predementia and AD. Protein expression of ß-amyloid (Aß), ß-secretase (BACE1), neprilysin (NEP), insulin degrading enzyme (IDE) and receptor for advanced glycation end products (RAGE) in the brain was measured. The results indicated that Al + D-gal induced an AD-like behavioral deficit at 90 days. The period from 45 to 75 days showed no significant behavioral deficit, and we tentatively define this as predementia in this model. A significant increase in BACE1 and decreasing NEP characterized days 45­90 in the cortex and hippocampus. However, high Aß occurred at day 60. IDE increased from day 60 to day 75. There was no change in RAGE. The results suggest that the observed changes in BACE1, NEP and Aß in predementia might relate to a different stage of the AD-like pathology, which may be developed into useful biomarkers for the diagnosis of very early AD.

Evaluation of functional MRI markers in mild cognitive impairment.

We aimed to investigate the use of advanced functional MRI (fMRI) techniques such as proton magnetic resonance spectroscopy ((1)H-MRS) and the apparent diffusion coefficient (ADC) value in diffusion weighted imaging (DWI), in the diagnosis of mild cognitive impairment (MCI). Multiple indicators were combined in order to improve the early diagnostic value of MRS and ADC. We administered MRS and DWI-ADC to 13 patients with Alzheimer's disease (AD), 9 patients with MCI, and 13 control patients. Changes in N-acetylaspartate/creatine and phosphocreatine (NAA/Cr), myoinositol/creatine (mI/Cr), and the ADC values in the hippocampus and the temporoparietal region were compared among groups. The sensitivity and specificity of different markers were analyzed individually and combined with others. All participants were evaluated by the mini mental state examination (MMSE), and the correlation between NAA/Cr, MI/Cr, ADC and the score of MMSE were analyzed separately. The NAA/Cr, mI/Cr and ADC values in the hippocampus among AD, MCI patients, and controls were significantly different (p<0.05). At a fixed specificity of 84.6%, the high sensitivity of 100% and 92.9% in differentiating AD and MCI from normal controls were obtained by combining the three indicators. The receiver operating characteristic plots illustrated that the area under the multimarker curve was the biggest among the all four curves, and the sensitivity of the multimarkers was highest. The best correlation was obtained between ADC and MMSE, rather than between NAA or mI and MMSE. Thus, we found that changes in NAA/Cr, mI/Cr and ADC in the hippocampus and the temporoparietal regions were helpful in the clinical diagnosis of MCI. Furthermore, these changes showed potential in predicting the progression of MCI to AD if the multimarkers were combined.

Altered expression of Abeta metabolism-associated molecules from D-galactose/AlCl(3) induced mouse brain.

Cerebral deposition of amyloid-beta peptide (Abeta) is a critical feature of Alzheimer's disease (AD). Either aluminium trichloride (Al) or D-galactose (D-gal) induces Abeta overproduction in rat or mouse brain and has been used to produce models of aging and AD. Here it is shown that mice treated with Al plus D-gal represent a good model of AD with altered expression of Abeta metabolism-associated molecules. The work shows that Al/D-gal causes memory impairment and high Abeta levels in the cortex (Co) and hippocampus (Hi). Then, we found that beta-site APP cleavage enzyme 1 (BACE1) was increased in mouse Co and Hi. Al or Al plus D-gal suppressed mRNA of the low-density lipoprotein receptor-related protein 1(LRP1). D-gal also decreased the LRP expression in Hi, but not in Co. However, Al/D-gal did not affect the receptor for advanced glycation end products (RAGE) expression in mouse brains. Furthermore, Al/D-gal reduced the expression of neprilysin (NEP), but not the insulin degrading enzyme (IDE). This study indicates that Al/D-gal affects the expression of Abeta metabolism-associated molecules that are responsible for Abeta deposition during AD, suggesting that this mouse model can be a useful model for studying the mechanisms and biomarkers of AD and for drug screening.