ABSTRACT
The amyloid precursor protein (APP) is the source of beta-amyloid, a pivotal peptide in the pathogenesis of Alzheimer's disease (AD). This study examines the possible effect of APP transgene expression on neuronal size by measuring the volumes of cortical neurons (microm(3)) in transgenic mouse models with familial AD Swedish mutation (APPswe), with or without mutated presenilin1 (PS1dE9), as well as in mice carrying wild-type APP (APPwt). Overexpression of APPswe and APPwt protein, but not of PS1dE9 alone, resulted in a greater percentage of medium-sized neurons and a proportionate decrease in the percentage of small-sized neurons. Our observations indicate that the overexpression of mutant (APPswe) or wild-type APP in transgenic mice is necessary and sufficient for hypertrophy of cortical neurons. This is highly suggestive of a neurotrophic effect and also raises the possibility that the lack of neuronal loss in transgenic mouse models of AD may be attributed to overexpression of APP.
Subject(s)
Amyloid beta-Protein Precursor/metabolism , Cell Size , Cerebral Cortex/cytology , Neurons/cytology , Receptors, Cell Surface/metabolism , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Cerebral Cortex/metabolism , Female , Male , Mice , Mice, Transgenic , Mutation , Neurons/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Protease Nexins , Receptors, Cell Surface/genetics , Sex CharacteristicsABSTRACT
Amyloid plaques are composed primarily of amyloid-beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) and are considered to play a pivotal role in Alzheimer's disease (AD) pathogenesis. Presently, AD is diagnosed after the onset of clinical manifestations. With the arrival of novel therapeutic agents for treatment of AD, there is an urgent need for biomarkers to detect early stages of AD. Measurement of plasma Abeta has been suggested as an inexpensive and non-invasive tool to diagnose AD and to monitor Abeta modifying therapies. However, the majority of cross-sectional studies on plasma Abeta levels in humans have not shown differences between individuals with AD compared to controls. Similarly, cross-sectional studies of mouse plasma Abeta have yielded inconsistent trends in different mouse models. However, longitudinal studies appear to be more promising in humans. Recently, efforts to modify plasma Abeta levels using modulators have shown some promise. In this review, we will summarize the present data on plasma Abeta in humans and mouse models of AD. We will discuss the potential of modulators of Abeta levels in plasma, including antibodies and insulin, and the challenges associated with measuring plasma Abeta. Modulators of plasma Abeta may provide an important tool to optimize plasma Abeta levels and may improve the diagnostic potential of this approach.
