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From the Nathan S. Kline Institute for Psychiatric
Research,*
Orangeburg, New York; the New York University
School of Medicine,
New York, New York; the
Department of Pathology (Neuropathology) and
Neurology,
The Johns Hopkins University
School of Medicine, Baltimore, Maryland; and the Department of
Neurology,§
Massachusetts General Hospital,
Boston, Massachusetts
Endocytosis is critical to the function and fate of molecules
important to Alzheimer’s disease (AD) etiology, including the
ß protein precursor (ßPP), amyloid ß (Aß)
peptide, and apolipoprotein E (ApoE). Early endosomes,
a major site of Aß 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 Aß 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. Markers of EP
activity were only minimally influenced by normal aging and other
neurodegenerative diseases studied. Inheritance of the 
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 Aß 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 Aß peptide generation and ApoE function, early
endosomal abnormalities provide a mechanistic link between EP
alterations, genetic susceptibility factors, and Aß
generation and suggest differences that may be involved in Aß
generation and ß amyloidogenesis in subtypes of AD.
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