Alzheimer's disease (AD) is a progressive neurological disorder and is thought to be initiated by accumulation of the AD-related proteins such as β-amyloid protein (Aβ) and phosphorylated tau. We previously showed that aging attenuates dynein-mediated retrograde transport, and dynein dysfunction reproduces age-dependent endocytic pathology such as intracellular accumulation of β-amyloid precursor protein (APP) in abnormally enlarged endosomes. In addition, endocytic dysfunction also causes intracellular accumulation of Aβ. Therefore, endocytic disturbance may be one of the causative factors for age-dependent AD pathology. Presenilin1 (PS1) is the catalytic core of gamma secretase complex which is required for Aβ cleavage. Thus, in this study, we investigated whether endocytic disturbance also affects PS1 localization and its function.
In aged monkey brains, the level of PS1 unchanged in microsome fraction even though APP clearly accumulated as previously reported. Our in vitro study also showed that endoyctic disturbance did not affect PS1 level in Neruo2a cells in contrast to APP. Moreover, endocytic diturbance did not alter neither subcellular distribution of PS1 nor γ-secretase complex formation. It is widely known that endocytic disturbance disrupts lysosomal degradation. Although the treatment of lysosomal inhibitor, ammonium chloride, potently induced intracellular accumulation of APP, we did not observe obvious change in PS1 level. These findings suggested that intracellular traffic of PS1 would be different from APP, and PS1 may not be mainly degraded in lysosome.