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

Paula I. Moreira, Quan Liu, Kazuhiro Honda, Mark A. Smith, Maria S. Santos, Catarina R. Oliveira
2004 Journal of Alzheimer's Disease  
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
more » ... y 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- tic pathology and dysfunction [4, 5] . Indeed, previous studies show that transgenic mice containing triple mutations for Aβ, PS1 and t, develop defects in longterm potentiation that correlate with the intraneuronal accumulation of Aβ before the appearance of amyloid plaques [5] . Indeed, in mouse models showing excessive amyloid deposition neuronal loss is modest even though the relative amyloid burden may be far greater than that found in patients with AD [6]. Furthermore, postmortem examination of many cognitively intact elderly individuals often reveals plaque loads above that found in many patients with AD. In addition, in AD the degree of cognitive impairment seems to be correlated with the total Aβ load rather the plaque load [7] . Several lines of evidence indicated that Aβ possesses trophic/antioxidant and pro-oxidant/toxic properties that are modulated by redox metal ions. The coordination of copper appears to be crucial for Aβ's own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma [8] . The only known catalytic activity of Aβ is the dismutation of O − 2 • to H 2 O 2 and tissues will only be protected from subsequent H 2 O 2 -mediated damage when the clearance mechanisms work properly. Thus, excessive accumulation of Aβ-copper may lead to an overproduction of H 2 O 2 that overwhelm the capacity of defence mechanisms to neutralize it. This would result
doi:10.3233/jad-2004-6411 fatcat:rhnxf577lbeprl3dgtparpdtwe