 |
 Previous Article | Next Article 
Journal of Neuroscience, Vol 16, 186-199, Copyright © 1996 by Society for Neuroscience
Properties of the endosomal-lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease
AM Cataldo, DJ Hamilton, JL Barnett, PA Paskevich and RA Nixon
Laboratories for Molecular Neuroscience, McLean Hospital, Belmont, Massachusetts, USA.
Specific antibodies and cytochemical markers combined with several imaging
and morphometric techniques were used to characterize the
endosomal-lysosomal system in mature neurons of the normal human central
nervous system and to quantitate changes in its function in Alzheimer's
disease. Compartments containing cathespin D (Cat D) and other acid
hydrolases included a major subpopulation of mature lysosomes lacking
mannose-6-phosphate receptors (MPR) and smaller populations of late
endosomes (MPR-positive) and lipofuscin granules (MPR-negative). Antibodies
to the pro-isoform of Cat D decorated perinuclear vacuolar compartments
corresponding to late endosomes. Neurons and glia contained lysosomes with
differing complements of acid hydrolases, implying different processing
capabilities. Endosome/lysosome number per unit volume of cytoplasm was
relatively well conserved within populations of normal neurons. By
contrast, in morphometric analyses of Alzheimer's disease brains, 80-93% of
pyramidal cells in the prefrontal cortex (laminae III or V) and hippocampus
(CA2, CA3) displayed two- to eightfold higher numbers of hydrolase-positive
vacuolar compartments than did corresponding cell populations in
age-matched normal brains. Only 5-10% of cerebellar Purkinje cells, a less
vulnerable population, showed the same statistically significant
elevations. Most affected in these brain regions and in subcortical areas
seemed otherwise normal by conventional histological staining and
ultrastructural inspection. That both lysosomal and pro-Cat D- and
MPR-positive endosomal compartments increased in number demonstrates that
the endosomal-lysosomal system is activated markedly in vulnerable neuronal
populations of Alzheimer's disease brains and implies that endocytosis or
autophagy or both are accelerated persistently at an early stage of
cellular compromise, greatly surpassing the degree of activity associated
with normal aging. Early activation of the endosomal-lysosomal system
represents a biological event potentially linking major etiological factors
in Alzheimer's disease, including defective membrane proteins,
apolipoprotein E function, and altered amyloid precursor protein
processing.
This article has been cited by other articles:
|
|
|
|
 
R. A. Nixon
Autophagy, amyloidogenesis and Alzheimer disease
J. Cell Sci.,
December 1, 2007;
120(23):
4081 - 4091.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Komatsu, Q. J. Wang, G. R. Holstein, V. L. Friedrich Jr., J.-i. Iwata, E. Kominami, B. T. Chait, K. Tanaka, and Z. Yue
Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration
PNAS,
September 4, 2007;
104(36):
14489 - 14494.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Fiala, P. T. Liu, A. Espinosa-Jeffrey, M. J. Rosenthal, G. Bernard, J. M. Ringman, J. Sayre, L. Zhang, J. Zaghi, S. Dejbakhsh, et al.
Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin
PNAS,
July 31, 2007;
104(31):
12849 - 12854.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Simonsen, R. C. Cumming, K. Lindmo, V. Galaviz, S. Cheng, T. E. Rusten, and K. D. Finley
Genetic Modifiers of the Drosophila Blue Cheese Gene Link Defects in Lysosomal Transport With Decreased Life Span and Altered Ubiquitinated-Protein Profiles
Genetics,
June 1, 2007;
176(2):
1283 - 1297.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Hawkes, D. Kabogo, A. Amritraj, and S. Kar
Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain
Am. J. Pathol.,
October 1, 2006;
169(4):
1140 - 1154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Offe, S. E. Dodson, J. T. Shoemaker, J. J. Fritz, M. Gearing, A. I. Levey, and J. J. Lah
The Lipoprotein Receptor LR11 Regulates Amyloid beta Production and Amyloid Precursor Protein Traffic in Endosomal Compartments
J. Neurosci.,
February 1, 2006;
26(5):
1596 - 1603.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Koike, M. Shibata, S. Waguri, K. Yoshimura, I. Tanida, E. Kominami, T. Gotow, C. Peters, K. von Figura, N. Mizushima, et al.
Participation of Autophagy in Storage of Lysosomes in Neurons from Mouse Models of Neuronal Ceroid-Lipofuscinoses (Batten Disease)
Am. J. Pathol.,
December 1, 2005;
167(6):
1713 - 1728.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Mizushima
A{beta} generation in autophagic vacuoles
J. Cell Biol.,
October 10, 2005;
171(1):
15 - 17.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Akazawa, S. Komazaki, H. Shimomura, F. Terasaki, Y. Zou, H. Takano, T. Nagai, and I. Komuro
Diphtheria Toxin-induced Autophagic Cardiomyocyte Death Plays a Pathogenic Role in Mouse Model of Heart Failure
J. Biol. Chem.,
September 24, 2004;
279(39):
41095 - 41103.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. L. Florez-McClure, D. A. Linseman, C. T. Chu, P. A. Barker, R. J. Bouchard, S. S. Le, T. A. Laessig, and K. A. Heidenreich
The p75 Neurotrophin Receptor Can Induce Autophagy and Death of Cerebellar Purkinje Neurons
J. Neurosci.,
May 12, 2004;
24(19):
4498 - 4509.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Guimaraes, M. Benchimol, G. P. Amarante-Mendes, and R. Linden
Alternative Programs of Cell Death in Developing Retinal Tissue
J. Biol. Chem.,
October 24, 2003;
278(43):
41938 - 41946.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Emiliani, L. Urbanelli, L. Racanicchi, A. Orlacchio, G. Pelicci, S. Sorbi, G. Bernardi, and A. Orlacchio
Up-regulation of Glycohydrolases in Alzheimer's Disease Fibroblasts Correlates with Ras Activation
J. Biol. Chem.,
October 3, 2003;
278(40):
38453 - 38460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. M. Grbovic, P. M. Mathews, Y. Jiang, S. D. Schmidt, R. Dinakar, N. B. Summers-Terio, B. P. Ceresa, R. A. Nixon, and A. M. Cataldo
Rab5-stimulated Up-regulation of the Endocytic Pathway Increases Intracellular {beta}-Cleaved Amyloid Precursor Protein Carboxyl-terminal Fragment Levels and A{beta} Production
J. Biol. Chem.,
August 15, 2003;
278(33):
31261 - 31268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. D. Finley, P. T. Edeen, R. C. Cumming, M. D. Mardahl-Dumesnil, B. J. Taylor, M. H. Rodriguez, C. E. Hwang, M. Benedetti, and M. McKeown
blue cheese Mutations Define a Novel, Conserved Gene Involved in Progressive Neural Degeneration
J. Neurosci.,
February 15, 2003;
23(4):
1254 - 1264.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-S. Ji, R. D. Miranda, Y. M. Newhouse, K. H. Weisgraber, Y. Huang, and R. W. Mahley
Apolipoprotein E4 Potentiates Amyloid beta Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells
J. Biol. Chem.,
June 7, 2002;
277(24):
21821 - 21828.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Mathews, C. B. Guerra, Y. Jiang, O. M. Grbovic, B. H. Kao, S. D. Schmidt, R. Dinakar, M. Mercken, A. Hille-Rehfeld, J. Rohrer, et al.
Alzheimer's Disease-related Overexpression of the Cation-dependent Mannose 6-Phosphate Receptor Increases Abeta Secretion. ROLE FOR ALTERED LYSOSOMAL HYDROLASE DISTRIBUTION IN beta -AMYLOIDOGENESIS
J. Biol. Chem.,
February 8, 2002;
277(7):
5299 - 5307.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Deng, M. C. Irizarry, R. M. Nitsch, J. H. Growdon, and G. W. Rebeck
Elevation of Cystatin C in Susceptible Neurons in Alzheimer's Disease
Am. J. Pathol.,
September 1, 2001;
159(3):
1061 - 1068.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Bi, A. P. Yong, J. Zhou, C. E. Ribak, and G. Lynch
Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice
PNAS,
June 28, 2001;
(2001)
151253098.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zhang, N. K. Dwyer, D. C. Love, A. Cooney, M. Comly, E. Neufeld, P. G. Pentchev, E. J. Blanchette-Mackie, and J. A. Hanover
Cessation of rapid late endosomal tubulovesicular trafficking in Niemann-Pick type C1 disease
PNAS,
April 10, 2001;
98(8):
4466 - 4471.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. B. Kegel, M. Kim, E. Sapp, C. McIntyre, J. G. Castano, N. Aronin, and M. DiFiglia
Huntingtin Expression Stimulates Endosomal-Lysosomal Activity, Endosome Tubulation, and Autophagy
J. Neurosci.,
October 1, 2000;
20(19):
7268 - 7278.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Cataldo, C. M. Peterhoff, J. C. Troncoso, T. Gomez-Isla, B. T. Hyman, and R. A. Nixon
Endocytic Pathway Abnormalities Precede Amyloid {beta} Deposition in Sporadic Alzheimer's Disease and Down Syndrome : Differential Effects of APOE Genotype and Presenilin Mutations
Am. J. Pathol.,
July 1, 2000;
157(1):
277 - 286.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Frautschy, D. L. Horn, J. J. Sigel, M. E. Harris-White, J. J. Mendoza, F. Yang, T. C. Saido, and G. M. Cole
Protease Inhibitor Coinfusion with Amyloid beta -Protein Results in Enhanced Deposition and Toxicity in Rat Brain
J. Neurosci.,
October 15, 1998;
18(20):
8311 - 8321.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Cataldo, J. L. Barnett, C. Pieroni, and R. A. Nixon
Increased Neuronal Endocytosis and Protease Delivery to Early Endosomes in Sporadic Alzheimer's Disease: Neuropathologic Evidence for a Mechanism of Increased beta -Amyloidogenesis
J. Neurosci.,
August 15, 1997;
17(16):
6142 - 6151.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Bednarski, C. E. Ribak, and G. Lynch
Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus
J. Neurosci.,
June 1, 1997;
17(11):
4006 - 4021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. McLaurin and A. Chakrabartty
Membrane Disruption by Alzheimer beta -Amyloid Peptides Mediated through Specific Binding to Either Phospholipids or Gangliosides. IMPLICATIONS FOR NEUROTOXICITY
J. Biol. Chem.,
October 25, 1996;
271(43):
26482 - 26489.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T.-F. Chan, P. G. Bertram, W. Ai, and X. F. S. Zheng
Regulation of APG14 Expression by the GATA-type Transcription Factor Gln3p
J. Biol. Chem.,
February 23, 2001;
276(9):
6463 - 6467.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Bi, A. P. Yong, J. Zhou, C. E. Ribak, and G. Lynch
Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice
PNAS,
July 17, 2001;
98(15):
8832 - 8837.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
