Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects.
Endocytic dysfunction is an early pathological change in Alzheimer's disease (AD) and Down's syndrome (DS). Using primary fibroblasts from DS individuals, we explored the interactions among endocytic compartments that are altered in AD and assessed their functional consequences in AD pathogenesis. We found that, like neurons in both AD and DS brains, DS fibroblasts exhibit increased endocytic uptake, fusion, and recycling, and trafficking of lysosomal hydrolases to rab5-positive early endosomes. Moreover, late endosomes identified using antibodies to rab7 and lysobisphosphatidic acid increased in number and appeared as enlarged, perinuclear vacuoles, resembling those in neurons of both AD and DS brains. In control fibroblasts, similar enlargement of rab5-, rab7-, and lysobisphosphatidic acid-positive endosomes was induced when endocytosis and endosomal fusion were increased by expression of either a rab5 or an active rab5 mutant, suggesting that persistent endocytic activation results in late endocytic dysfunction. Conversely, expression of a rab5 mutant that inhibits endocytic uptake reversed early and late endosomal abnormalities in DS fibroblasts. Our results indicate that DS fibroblasts recapitulate the neuronal endocytic dysfunction of AD and DS, suggesting that increased trafficking from early endosomes can account, in part, for downstream endocytic perturbations that occur in neurons in both AD and DS brains.
Cataldo
Anne M
AM
Laboratory for Molecular Neuropathology, Mailman Research Center, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA. acataldo@mclean.harvard.edu
Mathews
Paul M
PM
Boiteau
Anne Boyer
AB
Hassinger
Linda C
LC
Peterhoff
Corrinne M
CM
Jiang
Ying
Y
Mullaney
Kerry
K
Neve
Rachael L
RL
Gruenberg
Jean
J
Nixon
Ralph A
RA
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D001693:Biological Transport, Active; D002478:Cells, Cultured; D004314:Down Syndrome / Q000473:pathology*; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000473:pathology*; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D008875:Middle Aged; D050178:Monoglycerides / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D008246:Lysophospholipids; D050178:Monoglycerides; C012786:bis(monoacylglyceryl)phosphate; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D006867:Hydrolases; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins