PMID- 31278881
OWN - NLM
STAT- MEDLINE
DCOM- 20200327
LR  - 20200801
IS  - 1932-846X (Electronic)
IS  - 1932-8451 (Print)
IS  - 1932-8451 (Linking)
VI  - 79
IP  - 7
DP  - 2019 Jul
TI  - Enhanced generation of intraluminal vesicles in neuronal late endosomes in the 
      brain of a Down syndrome mouse model with endosomal dysfunction.
PG  - 656-663
LID - 10.1002/dneu.22708 [doi]
AB  - Down syndrome (DS) is a human genetic disease caused by trisomy of chromosome 21 
      and characterized by early developmental brain abnormalities. Dysfunctional 
      endosomal pathway in neurons is an early event of DS and Alzheimer's disease. 
      Recently, we have demonstrated that exosome secretion is upregulated in human DS 
      postmortem brains, in the brain of the trisomic mouse model Ts[Rb(12.17(16) 
      )]2Cje (Ts2) and by DS fibroblasts as compared with disomic controls. High levels 
      of the tetraspanin CD63, a regulator of exosome biogenesis, were observed in DS 
      brains. Partially blocking exosome secretion by DS fibroblasts exacerbated a 
      pre-existing early endosomal pathology. We thus hypothesized that enhanced CD63 
      expression induces generation of intraluminal vesicles (ILVs) in late 
      endosomes/multivesicular bodies (MVBs), increasing exosome release as an 
      endogenous mechanism to mitigate endosomal abnormalities in DS. Herein, we show a 
      high-resolution electron microscopy analysis of MVBs in neurons of the frontal 
      cortex of 12-month-old Ts2 mice and littermate diploid controls. Our quantitative 
      analysis revealed that Ts2 MVBs are larger, more abundant, and contain a higher 
      number of ILVs per neuron compared to controls. These findings were further 
      corroborated biochemically by Western blot analysis of purified endosomal 
      fractions showing higher levels of ILVs proteins in the same fractions containing 
      endosomal markers in the brain of Ts2 mice compared to controls. These data 
      suggest that upregulation of ILVs production may be a key homeostatic mechanism 
      to alleviate endosomal dysregulation via the endosomal-exosomal pathway.
CI  - (c) 2019 Wiley Periodicals, Inc.
FAU - D'Acunzo, Pasquale
AU  - D'Acunzo P
AUID- ORCID: 0000-0001-7237-0076
AD  - Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York.
AD  - Department of Psychiatry, New York University Langone Health, New York, New York.
FAU - Hargash, Tal
AU  - Hargash T
AD  - Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York.
FAU - Pawlik, Monika
AU  - Pawlik M
AD  - Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York.
FAU - Goulbourne, Chris N
AU  - Goulbourne CN
AD  - Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York.
FAU - Perez-Gonzalez, Rocio
AU  - Perez-Gonzalez R
AD  - Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York.
AD  - Department of Psychiatry, New York University Langone Health, New York, New York.
FAU - Levy, Efrat
AU  - Levy E
AD  - Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York.
AD  - Department of Psychiatry, New York University Langone Health, New York, New York.
AD  - Department of Biochemistry & Molecular Pharmacology, New York University Langone 
      Health, New York, New York.
AD  - Neuroscience Institute, New York University Langone Health, New York, New York.
LA  - eng
GR  - P01 AG017617/AG/NIA NIH HHS/United States
GR  - R01 AG056732/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20190801
PL  - United States
TA  - Dev Neurobiol
JT  - Developmental neurobiology
JID - 101300215
SB  - IM
MH  - Animals
MH  - Brain/*metabolism/pathology/ultrastructure
MH  - Disease Models, Animal
MH  - Down Syndrome/*metabolism/pathology
MH  - Endosomes/*metabolism/pathology/ultrastructure
MH  - Exosomes/*metabolism/pathology/ultrastructure
MH  - Female
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Neurons/*metabolism/pathology/ultrastructure
PMC - PMC6894426
MID - NIHMS1060855
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - CD63
OT  - Down syndrome
OT  - exosome
OT  - extracellular vesicles
COIS- The authors declare that they have no competing interests
EDAT- 2019/07/07 06:00
MHDA- 2020/03/28 06:00
PMCR- 2020/08/01
CRDT- 2019/07/07 06:00
PHST- 2019/01/30 00:00 [received]
PHST- 2019/07/01 00:00 [revised]
PHST- 2019/07/02 00:00 [accepted]
PHST- 2019/07/07 06:00 [pubmed]
PHST- 2020/03/28 06:00 [medline]
PHST- 2019/07/07 06:00 [entrez]
PHST- 2020/08/01 00:00 [pmc-release]
AID - 10.1002/dneu.22708 [doi]
PST - ppublish
SO  - Dev Neurobiol. 2019 Jul;79(7):656-663. doi: 10.1002/dneu.22708. Epub 2019 Aug 1.