Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

The effects of age, apolipoprotein E phenotype and gender on the concentration of amyloid-beta (A beta) 40, A beta 4242, apolipoprotein E and transthyretin in human cerebrospinal fluid.

OBJECTIVE: To test whether the concentrations of amyloid-beta (A beta) 40, A beta 42, apolipoprotein E (apoE) and transthyretin in the CSF of normal individuals, are linked to three factors which modulate the risk of Alzheimer's disease (AD): chronological age, gender, and the presence of the apoE4 allele. METHODS AND RESULTS: Proteins were measured by enzyme-linked immunosorbent assays except for transthyretin, which was assayed by radial immunodiffusion. The apoE phenotype was determined by isoelectric focusing. While the CSF levels of A beta 42, apoE, and transthyretin are reported to be reduced in AD, we found no relationship between age, gene, or apoE phenotype and the level of any of these proteins in the CSF of nondemented individuals. The concentration of A beta 40 was not modulated by gender or apoE phenotype, but did decline significantly with age. CONCLUSION: These results indicate that the changes observed in the CSF of AD patients are specific to the disease itself rather than the known risk factors.