Early Endosomal Abnormalities and Cholinergic Neuron Degeneration in Amyloid-β Protein Precursor Transgenic Mice

Early endosomal changes, a prominent pathology in neurons early in Alzheimer's disease, also occur in neurons and peripheral tissues in Down syndrome. While in Down syndrome models increased amyloid-beta protein precursor (A beta PP) expression is known to be a necessary contributor on the trisomic background to this early endosomal pathology, increased A beta PP alone has yet to be shown to be sufficient to drive early endosomal alterations in neurons. Comparing two A beta PP transgenic mouse models, one that contains the A beta PP Swedish K670N/M671L double mutation at the beta-cleavage site (APP23) and one that has the A beta PP London V717I mutation near the gamma-cleavage site (APPLd2), we show significantly altered early endosome morphology in fronto-parietal neurons as well as enlargement of early endosomes in basal forebrain cholinergic neurons of the medial septal nucleus in the APP23 model, which has the higher levels of A beta PP beta-C-terminal fragment (beta CTF) accumulation. Early endosomal changes correlate with a marked loss of the cholinergic population, which is consistent with the known dependence of the large projection cholinergic cells on endosome-mediated retrograde neurotrophic transport. Our findings support the idea that increased expression of A beta PP and A beta PP metabolites in neurons is sufficient to drive early endosomal abnormalities in vivo, and that disruption of the endocytic system is likely to contribute to basal forebrain cholinergic vulnerability.