Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome.
Early endosomes are a major site of amyloid precursor protein (APP) processing and a convergence point for molecules of pathologic relevance to Alzheimer's disease (AD). Neuronal endosome enlargement, reflecting altered endocytic function, is a disease-specific response that develops years before the earliest stage of AD and Down syndrome (DS). We examined how endocytic dysfunction is related to Abeta accumulation and distribution in early stage AD and DS. We found by ELISA and immunocytochemistry that the appearance of enlarged endosomes coincided with an initial rise in soluble Abeta40 and Abeta42 peptides, which preceded amyloid deposition. Double-immunofluorescence using numerous Abeta antibodies showed that intracellular Abeta localized principally to rab5-positive endosomes in neurons from AD brains and was prominent in enlarged endosomes. Abeta was not detectable in neurons from normal controls and was diminished after amyloid deposition in neuropathologically confirmed AD. These studies support growing evidence that endosomal pathology contributes significantly to Abeta overproduction and accumulation in sporadic AD and in AD associated with DS and may signify earlier disease-relevant disturbances of the signaling functions of endosomes.
Cataldo
Anne M
AM
Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. acataldo@mclean.harvard.edu
Petanceska
Suzana
S
Terio
Nicole B
NB
Peterhoff
Corrinne M
CM
Durham
Robert
R
Mercken
Marc
M
Mehta
Pankaj D
PD
Buxbaum
Joseph
J
Haroutunian
Vahram
V
Nixon
Ralph A
RA
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D004314:Down Syndrome / Q000378:metabolism* / Q000473:pathology*; D011992:Endosomes / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D021381:Protein Transport; D012720:Severity of Illness Index; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides