Is intraneuronal amyloid beta-peptide accumulation the trigger of Alzheimer's disease pathophysiology?

Using a double mutant transgenic rat model [amyloid precursor β protein (AβPP) and presenilin 1 (PS1) mutations], that stably expresses intracellular human amyloid β (Aβ) fragments, Lopez and colleagues [1] report that intracellular Aβ accumulation in hippocampus and neocortex induces morphological alterations in the Golgi apparatus and lysosomes and an increase in lipofuscin bodies. The authors suggest that the morphological alterations in the Golgi and lysosomes elements may be due to an increased activity of these elements associated with the processing of the high amount of AβPP present in the brain of the transgenic animals or to an increased activity related with the degradation of oxidative-damaged organelles. Furthermore, the increase in lipofuscin bodies observed by the authors supports the hypothesis of an increase in oxidativedamaged macromolecules. These data raise the issue of whether intracellular Aβ accumulation or oxidative stress is the trigger of Alzheimer’s disease (AD) pathophysiology. Despite the interesting results obtained by the authors, this problem remains unsolved. Intraneuronal Aβ accumulation has been directly observed in both human brain tissue and transgenic mice models [2,3] and has been associated with synap-