Quantitative histological analysis of amyloid deposition in Alzheimer's double transgenic mouse brain

The development of transgenic mice has created new opportunities for the ge neration of animal models of human neurodegenerative diseases where previou sly there was no animal counterpart. The first successful transgenic mouse model of Alzheimer's disease expressed increased levels of mutant human amy loid precursor protein, exhibiting neuritic-type amyloid deposits and behav ioral deficits at six to nine months of age. More recently, it was shown th at transgenic mice expressing both mutant human amyloid precursor protein a nd presenilin 1 exhibit neuritic-type amyloid deposits and behavioral defic its in as little as 12 weeks. This accelerated Alzheimer phenotype greatly reduces the time necessary to conduct preclinical drug trials, as well as a nimal housing costs. The purpose of this study was to quantify the depositi on of amyloid in five regions of the cortex and two regions of the hippocam pus of transgenic mice expressing amyloid precursor protein (K670N, M671L) and presenilin 1 (M146L) mutations at various ages, using quantitative meth ods of confocal laser scanning microscopy and image analysis. Amyloid burde n, expressed as the percentage area occupied by thioflavin S-positive amylo id deposits, increased an average of 179-fold from 12 to 54 weeks of age (0 .02 +/- 0.01% to 3.57 +/- 0.29%, mean +/- S.E.M., respectively) in five reg ions of the cortex and two of the hippocampus. This was a function of incre ases in both deposit number and size. This transgenic mouse provides an ideal animal model for evaluating the eff icacy of potential therapeutic agents aimed at reducing amyloid deposition, such as inhibitors of amyloid fibril formation or secretase inhibitors. (C ) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.