α‐Secretase cleaved amyloid precursor protein (APP) accumulates in cholinergic dystrophic neurites in normal, aged hippocampus

Aims Dystrophic neurites are associated with β‐amyloid ( A β) plaques in the brains of A lzheimer's disease ( AD ) patients and are also found in some specific areas of normal, aged brains. This study assessed the molecular characteristics of dystrophic neurites in normal ageing and its difference from AD . Methods We compared the dystrophic neurites in normal aged human brains (age 20–70 years) and AD brains ( B raak stage 4–6) by immunostaining against ChAT , synaptophysin, γ‐tubulin, cathepsin‐ D , A β1–16, A β17–24, amyloid precursor protein ( APP )‐ CT 695 and APP ‐ NT . We then tested the reproducibility in C 57 BL /6 mice neurone cultures. Results In normal, aged mice and humans, we found an increase in clustered dystrophic neurites of cholinergic neurones in CA 1 regions of the hippocampus and layer II and III regions of the entorhinal cortex, which are the major and earliest affected areas in AD . These dystrophic neurites showed accumulation of sAPP α peptides cleaved from the amyloid precursor protein by α‐secretase rather than A β or C ‐terminal fragments. In contrast, A β and APP ‐ CTFs accumulated in the dystrophic neurites in and around A β plaques of AD patients. Several experiments suggested that the accumulation of sAPP α resulted from ageing‐related proteasomal dysfunction. Conclusions Ageing‐associated impairment of the proteasomal system and accumulation of sAPP α at cholinergic neurites in specific areas of brain regions associated with memory could be associated with the normal decline of memory in aged individuals. In addition, these age‐related changes might be the most vulnerable targets of pathological insults that result in pathological accumulation of A β and/or APP ‐ CTFs and lead to neurodegenerative conditions such as AD .