Endocytic pathway abnormalities precede amyloid β deposition in sporadic Alzheimer's disease and Down syndrome -: Differential effects of APOE genotype and presenilin mutations

Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the beta protein precursor (PPP), amyloid beta (A beta) peptide, and apolipoprotein E (ApoE), Early endosomes, a major site of A beta peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes In the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as A beta deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markets of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the epsilon 4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenilin 1 or 2, indicating that altered endocytosis is not a consequence of A beta deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in A beta peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic Link between EP alterations, genetic susceptibility factors, and A beta generation and suggest differences that may be involved in A beta generation and beta amyloidogenesis in subtypes of AD.