Intraneuronal beta-amyloid is a major risk factor--novel evidence from the APP/PS1KI mouse model.

Accumulating evidence points to an important role of intraneuronal beta-amyloid (Abeta) in the development of Alzheimer's disease (AD), with its typical clinical symptoms like memory impairment and changes in personality. We have previously reported on the Abeta precursor protein and presenilin-1 knock-out (APP/PS1KI) mouse model with abundant intraneuronal Abeta(42) accumulation and a 50% loss of CA1 neurons at 10 months of age. In addition, we observed reduced short- and long-term synaptic plasticity, hippocampal neuron loss, and reduced performance in a working memory task. These observations support a pivotal role of intraneuronal Abeta accumulation as a principal pathological trigger in AD.