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Volume 17, Number 16,
Issue of August 15, 1997
pp. 6142-6151
Copyright ©1997 Society for Neuroscience
Increased Neuronal Endocytosis and Protease Delivery to Early
Endosomes in Sporadic Alzheimer's Disease: Neuropathologic Evidence
for a Mechanism of Increased  -Amyloidogenesis
Received Dec. 11, 1996; revised May 20, 1997; accepted May 23, 1997.
Anne M. Cataldo1, 2,
Jody L. Barnett1,
Cristiana Pieroni1, and
Ralph A. Nixon1, 2, 3
1 Laboratories for Molecular Neuroscience, McLean
Hospital, Belmont, Massachusetts 02178, 2 Departments of
Psychiatry and Neuropathology, and 3 Program in
Neuroscience, Harvard Medical School, Belmont, Massachusetts 02178
The early endosome is the first vacuolar compartment along the
endocytic pathway. It is the site of internalization and initial processing of amyloid precursor protein (APP) and apolipoprotein E
(ApoE), two proteins of etiological importance in Alzheimer's disease,
and a putative site of  -amyloid peptide (A) formation. Here, we
identify early endosomes in human pyramidal neurons, using specific
compartmental markers and morphometry, and show that in Alzheimer's
disease individual endosomes display up to 32-fold larger volumes than
the normal average. Endosomal enlargement contributed to an average
2.5-fold larger total endosomal volume per neuron, implying a marked
increase in endocytic activity. Endosomal alterations were evident in
most pyramidal neurons in Alzheimer brain, detectable at early stages
of the disease but absent in several other neurodegenerative disorders
examined. In addition, mature and proenzyme forms of the proteases
cathepsin B and cathepsin D, a candidate APP secretase, were identified in most early endosomes in Alzheimer brains but were detectable in only
a minor proportion of endosomes in normal brain. Expression of the
cation-dependent 46 kDa mannose 6-phosphate receptor was elevated in
pyramidal neurons of Alzheimer brains, which could be a possible basis
for the altered cathepsin trafficking pattern. Enhanced endocytic
activity, coupled with increased trafficking to endosomes of proteases,
which may have the ability under pathological conditions to generate
A, constitutes a potential mechanism by which -amyloidogenesis
may become accelerated in sporadic AD and also be subject to influences
by ApoE.
Key words:
endocytosis;
early endosome;
protease;
neurodegenerative
disease;
-amyloidogenesis;
lysosomal trafficking
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